Sulfonamide compounds

ABSTRACT

This invention relates to certain sulfonamide derivatives that are inhibitors of procollagen C-proteinase, pharmaceutical compositions containing them, methods for their use and methods for preparing these compounds.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. application Ser. No. 09/469,660filed Dec. 22, 1999, now U.S. Pat. No. 6,492,394.

This application claims the benefit under 35 U.S.C. 119(e) of U.S.Provisional Application Serial No. 60/113,311, filed Dec. 22, 1998; U.S.Provisional Application Serial No. 60/147,053, filed Aug. 3, 1999; andU.S. Provisional Application Serial No. 60/164,138, filed Nov. 8, 1999.All of the foregoing are hereby incorporated by reference in theirentirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to certain sufonamide derivatives thatinhibit procollagen C-proteinase, pharmaceutical compositions containingthem, methods for their use, and methods for preparing these compounds.

2. Background Information and Related Disclosures

The collagens are integral components of connective tissue. At presentnineteen types of collagens have been identified. The interstitialcollagen types I, II, and III are the major collagen components oftissue. These collagens are synthesized as procollagen precursormolecules having amino- and carboxy-terminal peptide extensions alsoknown as pro-regions. These pro-regions are typically cleaved uponsecretion of the procollagen molecule to give a mature collagen moleculewhich is capable of association into highly structured collagen fibers,((see, e.g., Fessler and Fessler, Annu. Rev. Biochem. 47, 129, (1978);Kivirikko et al., Extracellular Matrix Biochemistry (1984) and Kuhn,Structure and Function of Collagen Types (eds. Mayne, R and Burgeson, R.E.), Academic Press, Inc., Orlando, Fla., pp. 1-42 (1987)). It is wellestablished that excessive collagen deposition is associated with avariety of fibrotic diseases such as interstitial pulmonary fibrosis,pericentral fibrosis, Symmers' fibrosis, perimuscular fibrosis, kidneyfibrosis, endocardial sclerosis, hepatitis, acute respiratory distresssyndrome, arthritis, cystic fibrosis, tendon surgery, corneal scarring,surgical adhesions, scleroderma, chronic allograft rejection,hemodialysis shunt fibrosis, liver fibrosis and restenosis. Thesediseases are characterized by excessive deposits of fibrillarinterstitial collagens that are resistant to proteolytic degradationthus leading to the symptoms of fibrosis. Therefore, inhibition of thepathological deposition of these collagens should help in the treatmentof these diseases.

Recent studies suggest that C-proteinase is the essential enzyme thatcatalyzes the cleavage of the C-propeptide of types I, II, and IIIcollagens and is therefore instrumental in the formation of functionalcollagen fibers ((see, Fertala et al., J. Biol. Chem., 269, 11584,(1994)). It would therefore be desirable to provide procollagenC-proteinase inhibitors and thereby provide a means of combatingdiseases mediated by excessive deposition of these collagens. Thecompounds of this invention fulfill this and related needs.

SUMMARY OF THE INVENTION

In a first aspect, this invention provides sulfonamide derivativesselected from the group of compounds represented by Formula (I):

wherein:

Z is —OH, —NHOH, or OR¹² wherein R¹² is alkyl;

R¹ is alkyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, aralkyl,aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl,heterocyclylalkyl, cycloalkylalkyl, -(alkylene)-C(O)—X where X is alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino,disubstituted amino, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy, cycloalkoxy,cycloalkylalkoxy, heteroalkyloxy, aralkyloxy, or heteroaralkyloxy), or—C(═NR′)NHSO₂R″ (where R′ is hydrogen or alkyl, and R″ is alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, or heterocyclylalkyl);

R is —CH(R²)Ar¹ or —CH(R²)CH═CHAr¹ where R² is hydrogen or alkyl; andAr¹ is aryl or heteroaryl;

Ar² is either:

(i) a phenyl ring of formula (a):

wherein:

R³ and R⁷ are, independently of each other, hydrogen, alkyl, alkylthio,or halo;

R⁴ and R⁶ are, independently of each other, hydrogen, alkyl, or halo;

R⁵ is alkyl, haloalkyl, heterocyclyl, alkylthio, arylthio, aralkylthio,heteroarylthio, heteroaralkylthio, cycloalkylthio, cycloalkylalkylthio,alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyloxy, cycloalkoxy,cycloalkylalkoxy, alkyloxycarbonyl, hydroxy, halo, cyano, carboxy,nitro, amino, monoalkylamino, dialkylamino, alkylsulfonyl, arylsulfonyl,aralkylsulfonyl, heteroarylsulfonyl, heteroaralkylsulfonyl,cycloalkylsulfonyl, cycloalkylalkylsulfonyl, or —Y-(alkylene)-C(O)—Z[where Y is a bond, —NR^(a)—, —O—, or —S(O)_(n)— (where n is 0 to 2),R^(a) is hydrogen or alkyl, and Z is alkoxy, hydroxy, amino,monosubstituted amino, or disubstituted amino]; or

R⁵ together with R⁴ forms —O—(CR⁸R⁹)_(n)— where n is 2 or 3 and each R⁸and R⁹ are, independently of each other, hydrogen or alkyl; or

the carbon atoms to which R⁵ and R⁴ are attached are fused to the C2-C3carbons of a benzofuran ring;

provided that at least two of R³, R⁴, R⁶, and R⁷ are not hydrogen at thesame time; or

(ii) a naphthyl ring of formula (b):

wherein:

R¹⁰ is hydrogen, alkyl, alkoxy, or halo; and

R¹¹ is hydrogen, alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl,aryloxy, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino,dialkylamino or alkylsulfonyl provided that both R¹⁰ and R¹¹ are nothydrogen at the same time; and

their pharmaceutically acceptable salts, prodrugs, individual isomers,and mixtures of isomers.

Within the group of compounds represented by Formula (I), sulfonamidederivatives of this invention wherein Z is NHOH are represented byFormula (Ia):

In a second aspect, this invention provides a method of treatment of adisease treatable by administration of a therapeutically effectiveamount of a procollagen C-proteinase inhibitor of Formula (Ib) wherein:

wherein:

R¹ is alkyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, aralkyl,aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl,heterocyclylalkyl, cycloalkylalkyl, -(alkylene)-C(O)—X (where X isalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, amino, monosubstitutedamino, disubstituted amino, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy, cycloalkoxy,cycloalkylalkoxy, heteroalkyloxy, aralkyloxy, or heteroaralkyloxy), or—C(═NR′)NHSO₂R″ (where R′ is hydrogen or alkyl, and R″ is alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, or heterocyclylalkyl);

R is —CH(R²)Ar¹ or —CH(R²)CH═CHAr¹ where R² is hydrogen or alkyl; andAr¹ is aryl or heteroaryl;

Ar² is either:

(i) a phenyl ring of formula (a):

wherein:

R³ and R⁷ are, independently of each other, hydrogen, alkyl, alkylthio,or halo;

R⁴ and R⁶ are, independently of each other, hydrogen, alkyl, or halo;

R⁵ is alkyl, haloalkyl, heterocyclyl, alkylthio, arylthio, aralkylthio,heteroarylthio, heteroaralkylthio, cycloalkylthio, cycloalkylalkylthio,alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyloxy, cycloalkoxy,cycloalkylalkoxy, alkyloxycarbonyl, hydroxy, halo, cyano, carboxy,nitro, amino, monoalkylamino, dialkylamino, alkylsulfonyl, arylsulfonyl,aralkylsulfonyl, heteroarylsulfonyl, heteroaralkylsulfonyl,cycloalkylsulfonyl, cycloalkylalkylsulfonyl, or —Y-(alkylene)-C(O)—Z[where Y is a bond, —NR^(a)—, —O—, or —S(O)_(n)— (where n is 0 to 2),R^(a) is hydrogen or alkyl, and Z is alkoxy, hydroxy, amino,monosubstituted amino, or disubstituted amino]; or

R⁵ together with R⁴ forms —O—(CR⁸R⁹)_(n)— where n is 2 or 3 and each R⁸and R⁹ are, independently of each other, hydrogen or alkyl; or

the carbon atoms to which R⁵ and R⁴ are attached are fused to the C2-C3carbons of a benzofuran ring; or

(ii) a naphthyl ring of formula (b):

wherein:

R¹⁰ is hydrogen, alkyl, alkoxy, or halo; and

R¹¹ is hydrogen, alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl,aryloxy, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino,dialkylamino or alkylsulfonyl; and their pharmaceutically acceptablesalts, prodrugs, individual isomers, and mixtures of isomers.

In a third aspect, this invention provides pharmaceutical compositionscontaining a therapeutically effective amount of a compound of Formula(Ia) or (Ib) or its pharmaceutically acceptable salt and apharmaceutically acceptable excipient.

In a fourth aspect, this invention provides a process for preparingcompounds of Formula (Ia) or (Ib).

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in the specificationand claims have the meanings given below:

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms, e.g., methyl, ethyl, n-propyl,2-propyl, tert-butyl, pentyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene, propylene,2-methylpropylene, pentylene, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one double bond, e.g., ethenyl,propenyl, and the like.

“Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro andchloro.

“Haloalkyl” means alkyl substituted with one or more same or differenthalo atoms, e.g., —CH₂Cl, —CF₃, —CH₂CF₃, —CH₂CCl₃, and the like.

“Cycloalkyl” means a saturated monovalent cyclic hydrocarbon radical ofthree to seven ring carbons. The cycloalkyl may be optionallysubstituted independently with one, two, or three substituents selectedfrom alkyl, haloalkyl, halo, nitro, cyano, optionally substitutedphenyl, optionally substituted heteroaralkyl, —OR (where R is hydrogen,alkyl, or haloalkyl, —NRR′ (where R and R′ are independently hydrogen oralkyl), or —C(O)R (where R is hydrogen, alkyl, or optionally substitutedphenyl). More specifically, the term cycloalkyl includes, for example,cyclopropyl, cyclohexyl, 1,2-dihydroxycyclopropyl, and the like.

“Monosubstituted amino” means a radical —NHR where R is alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl, aralkyl,aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocyclyl, orheterocyclylalkyl, e.g., methylamino, ethylamino, phenylamine,benzylamine, dibenzylamine, and the like.

“Disubstituted amino” means a radical —NRR′ where R and R′ are,independently of each other, is alkyl, haloalkyl, cyanoalkyl,cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl, aralkyl, aralkenyl,heteroaryl, heteroaralkyl, heteroaralkenyl, heterocyclyl, orheterocyclylalkyl, or R and R′ together with the nitrogen atom to whichthey are attached form a heterocyclyl ring. Representative examplesinclude, but are not limited to, dimethylamino, methylethylamino,di(1-methyl-ethyl)amino, piperazinyl, and the like.

“Monoalkylamino” means a radical —NHR where R is alkyl, e.g.,methylamino, ethylamino, and the like.

“Dialkylamino” means a radical —NRR′ where R and R′ are independently ofeach other alkyl. Representative examples include, but are not limitedto, dimethylamino, methylethylamino, di(1-methylethyl)amino, and thelike.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbonradical of 6 to 10 ring atoms which is substituted independently withone or more substituents, preferably one, two, or three substituentsselected from alkyl, haloalkyl, thioalkyl, heteroalkyl, halo, nitro,cyano, optionally substituted phenyl, heteroaryl, heterocyclyl, hydroxy,alkoxy, haloalkoxy, optionally substituted phenyloxy, heteroaryloxy,methylenedioxy, ethylenedioxy, —COR (where R is alkyl or optionallysubstituted phenyl), -(alkylene)_(n)-COOR (where n is 0 or 1 and R ishydrogen, alkyl, optionally substituted phenylalkyl, or heteroaralkyl),—NR^(a)R^(b) (where R^(a) and R^(b) are independently of each other,hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, optionallysubstituted phenyl, or heteroaryl), —NR^(a)COR^(b) (where R^(a) ishydrogen or alkyl and R^(b) is hydrogen, alkyl, haloalkyl, or optionallysubstituted phenyl), —S(O)_(n)R [where n is an integer from 0 to 2 and Ris hydrogen (provided that n is 0), alkyl, cycloalkyl, cycloalkylalkyl,heteroalkyl, optionally substituted phenyl, optionally substitutedphenylalkyl, or heteroaryl], —SO₂NR^(a)R^(b) (where R^(a) and R^(b) are,independently of each other hydrogen, alkyl, hydroxyalkyl, or optionallysubstituted phenyl, or R^(a) and R^(b) together with the nitrogen atomto which they are attached form a heterocyclyl ring), —NRSO₂R′ (where Ris hydrogen or alkyl and R′ is alkyl, cycloalkyl, cycloalkylalkyl,heteroalkyl, optionally substituted phenyl, optionally substitutedphenylalkyl, or heteroaryl), —NRSO₂NR′R″ (where R is hydrogen or alkyland R′ and R″ are, independently of each other, hydrogen, alkyl, orhydroxyalkyl, or R′ and R″ together with the nitrogen atom to which theyare attached form a heterocyclyl ring), or -(alkylene)_(n)-CONR^(a)R^(b)(where n is 0 or 1, and R^(a) and R^(b) are, independently of eachother, hydrogen or alkyl, or R^(a) and R^(b) together with the nitrogenatom to which they are attached form a heterocyclyl ring). Morespecifically the term aryl includes, but is not limited to, phenyl,1-naphthyl, and 2-naphthyl, and the derivatives thereof.

“Optionally substituted phenyl” means a phenyl ring which is optionallysubstituted independently with one or more substituents, preferably oneor two substituents selected from alkyl, haloalkyl, thioalkyl,hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy,alkoxycarbonyl, amino, methylenedioxy, ethylenedioxy, —COR (where R isalkyl), —COOR (where R is alkyl), —NR^(a)R^(b) (where R^(a) and R^(b)are independently of each other hydrogen or alkyl), —NR^(a)COR^(b)(where R^(a) is hydrogen or alkyl and R^(b) is alkyl, haloalkyl, oroptionally substituted phenyl), or —CONR^(a)R^(b) (where R^(a) and R^(b)are independently of each other hydrogen or alkyl). More specificallythe term aryl includes, but is not limited to, phenyl, 1-napthyl, and2-naphthyl, and the derivatives thereof.

“Heteroaryl” means a monovalent monocyclic or bicyclic aromatic radicalof 5 to 12 ring atoms containing one, two, or three ring heteroatomsselected from N, O, or S, the remaining ring atoms being C. Theheteroaryl ring is optionally substituted independently with one or moresubstituents, preferably one or two substituents, selected from alkyl,haloalkyl, heteroalkyl, heterocyclyl, halo, nitro, cyano, —OR (where Ris hydrogen, alkyl, haloalkyl, optionally substituted phenyl, oroptionally substituted heteroaryl), —NRR′ (where R and R′ are,independently of each other, hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, hydroxyalkyl, or optionally substituted phenyl), —C(O)R(where R is hydrogen, alkyl, or optionally substituted phenyl),-(alkylene)_(n)-COOR (where n is 0 or 1 and R is hydrogen, alkyl,optionally substituted phenylalkyl, or optionally substitutedheteroaralkyl), —S(O)_(n)R [where n is an integer from 0 to 2 and R ishydrogen (provided that n is 0), alkyl, cycloalkyl, cycloalkylalkyl,heteroalkyl, optionally substituted phenyl, optionally substitutedphenylalkyl, or optionally substituted heteroaryl], —SO₂NR′R″ (where R′and R″ are, independently of each other, hydrogen, alkyl, hydroxyalkyl,or optionally substituted phenyl, or R′ and R″ together with thenitrogen atom to which they are attached form a heterocyclyl ring),—NRC(O)R′ (where R is hydrogen or alkyl and R′ is alkyl, haloalkyl, oroptionally substituted phenyl), —NRSO₂R′ (where R is hydrogen or alkyland R′ is alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, optionallysubstituted phenyl, optionally substituted phenylalkyl, or optionallysubstituted heteroaryl), —NRSO₂NR′R″ (where R is hydrogen or alkyl, andR′ and R″ are, independently of each other, hydrogen or alkyl, or R′ andR″ together with the nitrogen atom to which they are attached form aheterocyclyl ring), -(alkylene)_(n)-CONR′R″ (where n is 0 or 1 and R′and R″ are, independently of each other, hydrogen or alkyl, or R′ and R″together with the nitrogen atom to which they are attached form aheterocyclyl ring), or an amino protecting group. More specifically theterm heteroaryl includes, but is not limited to, pyridyl, furanyl,thiophenyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl,pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, isobenzofuranyl,benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl,benzoxazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzisoxazolyl,benzothiophenyl, dibenzofuran, and benzodiazepin-2-one-5-yl, and thederivatives thereof.

“Heterocyclyl” means a saturated cyclic radical of 3 to 8 ring atoms inwhich one or two ring atoms are heteroatoms selected from N, O, orS(O)_(n) (where n is an integer from 0 to 2), the remaining ring atomsbeing C, where one or two C atoms may optionally be replaced by acarbonyl group. The heterocyclo ring may be optionally substitutedindependently with one, two, or three substituents selected from alkyl,haloalkyl, halo, nitro, cyano, optionally substituted phenyl, optionallysubstituted heteroaryl, optionally substituted phenyalkyl, optionallysubstituted heteroaralkyl, —OR (where R is hydrogen, alkyl, orhaloalkyl), —NRR′ (where R and R′ are independently hydrogen or alkyl),—C(O)R (where R is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, oraryloxyalkyl), —COOR (where R is hydrogen, alkyl, aryl, aralkyl,heteroaralkyl), -(alkylene)-COOR (where R is hydrogen, alkyl, optionallysubstituted phenyl, optionally substituted phenyalkyl, or optionallysubstituted heteroaralkyl), —CONR′R″, or -(alkylene)-COONR′R″ (where R′and R″ are independently selected from hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl), —S(O)_(n)R(where n is an integer from 0 to 2 and R is hydrogen (provided that n is0) or alkyl), alkoxycarbonyl, —NRC(O)R′ (where R is hydrogen or alkyland R′ is hydrogen or alkyl), —NRSO₂R′ (where R is hydrogen or alkyl andR′ is alkyl), —NRSO₂NR′R″ (where R, R′ and R″ are independently hydrogenor alkyl), or an amino protecting group. The heterocyclo ring also maybe optionally fused with an aryl ring as defined above. Morespecifically the term heterocyclo includes, but is not limited to,tetrahydropyranyl, piperidino, piperazino, morpholino andthiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, andthe derivatives thereof.

“Heteroalkyl” means an alkyl, cycloalkyl, or cycloalkylalkyl radical asdefined above, carrying a substituent selected from —NR^(a)R^(b),—OR^(c), or —S(O)_(n)R^(d) wherein n is an integer from 0 to 2, R^(a) ishydrogen, alkyl, or —COR (where R is hydrogen, alkyl, or haloalkyl);R^(b) is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,heterocyclyhydroxyalkyl, —COR (where R is hydrogen, alkyl, haloalkyl,monosubstituted aminoalkyl, aryloxyalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylalkyl, or-(alkylene)-C(O)—X (where X is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino,aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, orheterocyclyalkyl), —SO₂R (where R is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,heterocyclylalkyl, amino, monosubstituted amino or disubstituted amino),—COOR (where R is hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, orheterocyclylalkyl), —CONR′R″, or -(alkylene)-CONR′R″ [where R′ and R″are independently selected from hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl,or SO₂R (where R is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,amino, monosubstituted amino or disubstituted amino), or R′ and R″together with the nitrogen atom to which they are attached form aheterocyclyl ring]; R^(c) is hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclylalkyl, —COR (where R is alkyl, haloalkyl, or heterocyclyl),or —CONR′R″ (where R′ and R″ are independently selected from hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl); and R^(d) is hydrogen (provided that n is 0), alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, amino, monosubstituted amino, ordisubstituted amino. Representative examples include, but are notlimited to hydroxymethyl, 2-hydroxyethyl, 2-methoxyethyl,benzyloxymethyl, thiophen-2-ylthiomethyl, and the like;

“Aralkyl” means a radical —R^(a)R^(b) where R^(a) is an alkylene groupand R^(b) is an aryl group as defined above e.g., benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like.

“Aralkenyl” means a radical —R^(a)R^(b) where R^(a) is an alkenyl groupand R^(b) is an aryl group as defined above e.g., 3-phenyl-2-propenyl,and the like.

“Heteroaralkyl” means a radical —R^(a)R^(b) where R^(a) is an alkylenegroup and R^(b) is a heteroaryl group as defined above e.g.,pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.

“Heteroaralkenyl” means a radical —R^(a)R^(b) where R^(a) is an alkenylgroup and R^(b) is a heteroaryl group as defined above e.g.,3-pyridin-3-ylpropen-2-yl, and the like.

“Heterocyclylalkyl” means a radical —R^(a)R^(b) where R^(a) is analkylene group and R^(b) is a heterocyclyl group as defined above e.g.,tetrahydropyran-2-ylmethyl, 4-methylpiperazin-1-ylethyl, 2-, or3-piperidinylmethyl, and the like.

“Cycloalkylalkyl” means a radical —R^(a)R^(b) where R^(a) is an alkylenegroup and R^(b) is a cycloalkyl group as defined above e.g.,cyclopropylmethyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, andthe like.

“Alkoxy”, “aryloxy”, “aralkyloxy”, or “heteroaralkyloxy” means a radical—OR where R is an alkyl, aryl, aralkyl, or heteroaralkyl respectively,as defined above e.g., methoxy, phenoxy, pyridin-2-ylmethyloxy,benzyloxy, and the like.

“Hydroxyalkyl” means an alkyl radical as defined above, carrying one ormore, preferably one, two or three hydroxy groups, provided that if twohydroxy groups are present they are not both on the same carbon atom.Representative examples include, but are not limited to, 2-hydroxyethyl,2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl,2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl,1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyland 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “heterocyclo group optionally mono-or disubstituted with an alkyl group” means that the alkyl may but neednot be present, and the description includes situations where theheterocyclo group is mono- or disubstituted with an alkyl group andsituations where the heterocyclo group is not substituted with the alkylgroup.

“Amino protecting group” refers to those organic groups intended toprotect nitrogen atoms against undesirable reactions during syntheticprocedures e.g., benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl(Boc), trifluoroacetyl, 2-trimethylsilyl-ethanesulfonyl (SES), and thelike.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers”. Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example,where a carbon atom is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequence rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art (see discussion in Chapter 4 of “Advanced OrganicChemistry”, 4th edition J. March, John Wiley and Sons, New York, 1992).

A “pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes an excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include:

(1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or

(2) salts formed when an acidic proton present in the parent compoundeither is replaced by a metal ion, e.g., an alkali metal ion, analkaline earth ion, or an aluminum ion; or coordinates with an organicbase such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like.

“Pro-drugs” means any compound which releases an active parent drugaccording to formula (I) in vivo when such prodrug is administered to amammalian subject. Prodrugs of a compound of formula (I) are prepared bymodifying functional groups present in the compound of formula (I) insuch a way that the modifications may be cleaved in vivo to release theparent compound. Prodrugs include compounds of formula (I) wherein ahydroxy, amino, or sulfhydryl group in compound (I) is bonded to anygroup that may be cleaved in vivo to regenerate the free hydroxyl,amino, or sulfhydryl group, respectively. Examples of prodrugs include,but are not limited to esters (e.g., acetate, formate, and benzoatederivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxyfunctional groups in compounds of formula (1), and the like.

“Treating” or “treatment” of a disease includes:

(1) preventing the disease, i.e. causing the clinical symptoms of thedisease not to develop in a mammal that may be exposed to or predisposedto the disease but does not yet experience or display symptoms of thedisease,

(2) inhibiting the disease, i.e., arresting or reducing the developmentof the disease or its clinical symptoms, or

(3) relieving the disease, i.e., causing regression of the disease orits clinical symptoms.

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

Nomenclature

The naming and numbering of the compounds of this invention isillustrated below.

The nomenclature used in this application is generally based on theIUPAC recommendations, e.g., a compound of formula (Ia):

where R¹ is —CH(CH₃)₂, R is —CH(R²)Ar¹ wherein R² is hydrogen, Ar¹ is3,4-methylenedioxyphenyl, Ar² is 4-methoxyphenyl and the stereochemistryat the carbon to which R¹ is attached is (R) is named,N-hydroxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyramide.

where R¹ is —CH₂OH, R is —CH(R²)Ar¹ wherein R² is hydrogen, Ar¹ isindol-5-yl, Ar² is 2,3,6-trimethyl-4-methoxyphenyl and thestereochemistry at the carbon to which R¹ is attached is (R) is named,N-hydroxy-2(R)-[(1H-indol-5-ylmethyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-hydroxypropionamide.

Representative compounds of this invention are as follows:

Compounds of Formula (Ia) and (Ib) wherein R is —CH(R²)Ar¹ and the othergroups are defined as follows:

CPD Stereo- Mass Spec. # chem at *C R² R¹ Ar¹ Ar² M. Pt ° C. MH+ 1 (R) H2-propyl indol-5-yl 4-methoxyphenyl 105-107 439 2 (R) H (CH₃)₂CHCH₂3,4-methylenedioxyphenyl 4-bromophenyl 117.8-119.2 499 3 (R) H 2-propyl3,4-methylenedioxyphenyl 2-methoxy-6-naphthyl 152-153 487 4 (R) HCH₃CO₂CH₂ 3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 78-81 547methoxyphenyl 5 (R) H hydroxymethyl 3,4-methylenedioxyphenyl2,3,6-trimethyl-4- 167.3-168.1 467 methoxyphenyl 6 (R) H 2-propyl3,4-dihydroxyphenyl 4-methoxyphenyl 88.5-92   425 7 (R) H 2-propyl3,4-methylenedioxyphenyl 4-chlorophenyl 441 8 (R) H 2-propyl3,4-methylenedioxyphenyl 4-methoxyphenyl 162.3-163.6 437 9 (R) H2-propyl 3,4-methylenedioxyphenyl 4-bromophenyl 485 10 (R) H benzyl3,4-methylenedioxyphenyl 4-methoxyphenyl 485 11 (R) H 2-propylindol-5-yl 2,3,6-trimethyl-4- 103-106 474 methoxyphenyl 12 (R) H2-propyl 3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 129-131 479methoxyphenyl 13 (R) H 2-propyl 3,4-dihydroxyphenyl2,2,5,7,8-pentamethyl- 144-146 521 chroman-6-yl 14 (R) H hydroxymethyl3,4-methylenedioxyphenyl 2,5-dimethyl-4- 457 chlorophenyl 15 (R) H tert-indol-5-yl 2,3,6-trimethyl-4- 517 butoxymethyl methoxyphenyl 16 (R) H2-propyl 3,4-methylenedioxyphenyl dibenzofuran-4-yl 172.5-175   497 17(RS) H ethyl 3,4-methylenedioxyphenyl 4-bromophenyl 471 18 (RS) CH₃ethyl 3,4-methylenedioxyphenyl 4-bromophenyl 485 19 (R) H 2-propyl3,4-methylenedioxyphenyl 2,5-dimethyl-4- 466 chlorophenyl 20 (R) H2-hydroxyethyl 3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 481methoxyphenyl 21 (R) H 2-propyl 4-(CH₃OCO)phenyl 4-methoxyphenyl 164-165451.1 22 (R) H 2-propyl 1-(methyl)indol-5-yl 2,3,6-trimethyl-4- 486methoxyphenyl 23 (R) H 2-propyl 3-nitro-4-methylphenyl 4-methoxyphenyl452 24 (R) H tert- 3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 523butoxymethyl methoxyphenyl 25 (R) H 2-propyl 3-fluorophenyl4-methoxyphenyl 159.8-162.8 411 26 (R) H hydroxymethyl indol-5-yl2,5-dimethyl-4- 448 methoxyphenyl 27 (R) H 2-propyl 3-hydroxy-4-methoxy-4-methoxyphenyl 439 phenyl 28 (R) H 2-propyl 4-hydroxyphenyl4-methoxyphenyl 409 29 (R) H PhCONHCH₂ 4-(CH₃OCO)phenyl 4-methoxyphenyl542 30 (R) H 2-propyl 3,4-methylenedioxyphenyl 2-methyl-4-bromophenyl499 31 (R) H 2-propyl 4-methylphenyl 4-methoxyphenyl 169.6-170.5 407 32(R) H (CH₃)₂CHCH₂ 3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 137-138493.21 methoxyphenyl (HRMS) 33 (R) H 2-propyl 3,4-methylenedioxyphenyl2,3,5,6-tetramethylphenyl 463 34 (R) H benzyl indol-5-yl2,3,6-trimethyl-4- 522 methoxyphenyl 35 (R) H 2-propyl benzimidazol-5-yl4-methoxyphenyl 433 36 (R) H 2-propyl 3,4-methylenedioxyphenyl2,5-dimethyl-4- 465 methoxyphenyl 37 (R) H methoxymethyl3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 481 methoxyphenyl 38 (R) H2-propyl 2-(methyl) 4-methoxyphenyl 447 benzimidazol-5-yl 39 (R) H2-propyl benzoxazol-5-yl 4-methoxyphenyl 434 40 (R) H 2-propyl3,4-methylenedioxyphenyl 2,6-dimethyl-4- 465 methoxyphenyl 41 (R) Hhydroxymethyl indol-5-yl 2,5-dimethyl-4- 452 chlorophenyl 42 (R) H2-propyl 3,4-methylenedioxyphenyl 4-methylthiophenyl 453 43 (R) H2-propyl 4-hydroxymethylphenyl 4-methoxyphenyl  96-100 423 44 (R) H2-propyl 3-amino-4-hydroxyphenyl 2,3,6-trimethyl-4-   64-65.5 465methoxyphenyl 45 (R) H C₆H₅SO₂NHCH₂ 4-(CH₃OCO)phenyl 4-methoxyphenyl 57846 (R) H 2-propyl 4-(C₆H₅SO₂NH)phenyl 4-methoxyphenyl 167.2-169.1 548 47(R) H indol-3-yl 3,4-methylenedioxyphenyl 4-methoxyphenyl 524 methyl 48(R) H C₆H₅CONH 3-nitrophenyl 4-methoxyphenyl 529 CH₂ 50 (R) H phenyl3,4-methylenedioxyphenyl 4-methoxyphenyl 471 51 (R) H 2-propyl4-(CH₃CO)phenyl 4-methoxyphenyl   164-164.9 435 52 (R) H 2-propyl3,4-ethylenedioxyphenyl 4-methoxyphenyl   141-144.5 451 53 (R) H2-[4-(benzyloxy- 3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 711.4carbonyl)piperazin-1-yl methoxyphenyl carbonyl]ethyl 54 (R) H2-(pyridin-3-yl- 3-fluorophenyl 4-methoxyphenyl 531.2 methylamino-carbonyl)ethyl 55 (R) H 2-[4-phenyl- 3-nitro-4-methylphenyl4-methoxyphenyl 626.4 piperazin-1-yl- carbonyl]ethyl 56 (R) H2-[4-(methoxy- 3,4-methylenedioxyphenyl 4-methoxyphenyl 621.2carbonyl)piperazin-1-yl carbonyl]ethyl 57 (R) H 2-[4-acetylpiperazin-3-fluorophenyl 2,3,6-trimethyl-4- 593.4 1-yl-carbonyl]ethylmethoxyphenyl 58 (R) H 2-[4-(ethoxy- 3,4-methylenedioxyphenyl2,3,6-trimethyl-4- 649.4 carbonyl)piperazin-1-yl methoxyphenylcarbonyl]ethyl 59 (R) H 2-[4-(ethoxy- 3-fluorophenyl 4-methoxyphenyl581.2 carbonyl)piperazin-1-yl carbonyl]ethyl 60 (R) H2-[1-(ethoxycarbonyl) 3,4-methylenedioxyphenyl 4-methoxyphenyl 621.2piperidin-4-yl aminocarbonyl]ethyl 61 (R) H 2-(thiomorpholin-3,4-methylenedioxyphenyl 4-methoxyphenyl 552.2 4-ylcarbonyl)ethyl 62 (R)H 2-[1-(ethoxycarbonyl) 3,4-methylenedioxyphenyl 2,3,6-trimethyl-4-663.2 piperidin-4-yl methoxyphenyl aminocarbonyl]ethyl 63 (R) H2-(benzylamino- 3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 598.2carbonyl]ethyl methoxyphenyl 64 (R) H 2- [4-phenyl)piperazin-3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 653.4 1-yl-carbonyl]ethylmethoxyphenyl 65 (R) H 2-[4-(pyridin-2-yl)- 3-fluorophenyl4-methoxyphenyl 586.2 piperazin-1-yl- carbonyl]ethyl 66 (R) H2-(4-pyridin-4-yl- 3-fluorophenyl 4-methoxyphenyl 531.2 methylamino-carbonyl)ethyl 67 (R) H 2-(benzylamino- 3-fluorophenyl 4-methoxyphenyl530.2 carbonyl)ethyl 68 (R) H 2-[4-(pyridin-2-yl)- 3-fluorophenyl2,3,6-trimethyl-4- 628.4 piperazin-1-yl- methoxyphenyl carbonyl]ethyl 69(R) H 2-(4-acetylpiperazin- 3-fluorophenyl 4-methoxyphenyl 551.21-ylcarbonyl)ethyl 70 (R) H 2-(4-acetylpiperazin-3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 619.4 1-ylcarbonyl)ethylmethoxyphenyl 71 (R) H 2-[1-(ethoxycarbonyl) 3-fluorophenyl2,3,6-trimethyl-4- 637.4 piperidin-4-yl methoxyphenylaminocarbonyl]ethyl 72 (R) H benzyl 3,4-methylenedioxyphenyl2,3,6-trimethyl-4- 493.2063 methoxy-phenyl (HRMS) 73 (R) H 2-propyl3,4-methylenedioxyphenyl 4,8-dimethoxynapth-1-yl 517 74 (R) H 2-propylcinnamyl 4-methoxyphenyl 419 75 (R) H hydroxymethyl indol-5-yl2,6-dimethyl-4- 448 methoxyphenyl 76 (R) H hydroxymethyl3,4-methylenedioxyphenyl 2,6-dimethyl-4-   164-165.9 453 methoxyphenyl77 (R) H (CH₃)₂CH CH₂— 3,4-methylenedioxyphenyl 2,3,6-trimethyl-4-137-138 478.19 methoxyphenyl 78 (R) H 2-propyl indol-5-yl2,6-dimethyl-4- 115-121 460 methoxyphenyl 79 (R) H hydroxymethyl3,4-methylenedioxyphenyl 2,5-dimethyl-4-   135-147.2 433 methoxyphenyl80 (R) H 1-hydroxyethyl indo-5-yl 2,3,6-trimethyl-4- 409 methoxyphenyl81 (R) H 2-propyl 3-[1-(hydroximino)propyl] 2,3,6-trimethyl-4- 545indol-5-yl methoxyphenyl 82 (R) H 2-propyl benzimidazol-5-yl2,5,6-trimethyl-4- 475 methoxyphenyl 83 (R) H 2-[4-(4-methylphenyl-3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 710.8aminocarbonyl)-piperazin- methoxyphenyl 1-yl-carbonyl]ethyl 84 (R) H2-[4-(3-methoxyphenyl- 3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 726.8aminocarbonyl)-piperazin- methoxyphenyl 1-yl-carbonyl]ethyl 85 (R) Hbenzyl indol-5-yl 2,3,6-trimethyl-4- 522.21 methoxyphenyl 86 (R) Hhydroxymethyl indol-5-yl 2,3,6-trimethyl-4- 462.17 methoxyphenyl 87 (R)H 1-hydroxyethyl 3,4-methylenedioxyphenyl 2,3,6-trimethyl-4-  95-105 481methoxyphenyl 88 (R) H 2-propyl 3-[(N-benzyloxy)methyl2,3,6-trimethyl-4- 621 imidoyl]indol-5-yl methoxyphenyl 89 (R) H2-(N-methylethyl 3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 550.6aminocarbonyl)ethyl methoxyphenyl 90 (R) H 2-[4-acetyl-3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 619.7 piperazin-1-yl-methoxyphenyl carbonyl]ethyl 91 (R) H 2-[4-(phenoxymethyl-3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 711.8 carbonyl)piperazin-methoxyphenyl 1-yl-carbonyl]ethyl 92 (R) H methoxymethyl indol-5-yl2,3,6-trimethyl-4- 476 methoxyphenyl 93 (R) H 2[4-(methane sulfonyl)-3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 655.8 piperazin-1-yl-methoxyphenyl carbonyl]ethyl 94 (R) H 2-hydroxyethyl3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 481.17 methoxyphenyl 95 (R)H 2-(cyclopropyl 3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 548.6aminocarbonyl)ethyl methoxyphenyl 96 (R) H 2-[4-benzyloxy3,4-methylenedioxyphenyl 2,3,6-trimethyl-4- 711.8 carbonylpiperazin-methoxyphenyl 1-yl-carbonyl]ethyl 97 (R) H 4-(methoxy3,4-methylenedioxyphenyl 4-methoxyphenyl 586.6 carbonyl)phenylcarbonylaminomethyl 98 (R) H 3-(benzyloxy 3,4-methylenedioxyphenyl4-methoxyphenyl 586 carbonylamino)propyl 99 (R) H 2-(pyrrol-1-yl)3,4-methylenedioxyphenyl 4-methoxyphenyl 593.6 phenylcarbonylaminomethyl 100 (R) H 2-[(diphenyl) 3,4-methylenedioxyphenyl4-methoxyphenyl 632.7 methylamino carbonyl]ethyl 101 (R) H 3-cyanophenyl3,4-methylenedioxyphenyl 4-methoxyphenyl 568.6 aminocarbonyl aminomethyl102 (R) H thien-2-yl 3,4-methylenedioxyphenyl 4-methoxyphenyl 534.6carbonylaminomethyl 103 (R) H phenylcarbonyl 3,4-methylenedioxyphenyl4-methoxyphenyl 528.6 aminomethyl 104 (R) H (C₆H₅)CHCH₃N3,4-methylenedioxyphenyl 4-methoxyphenyl 627.7 HCO(C₂H₄)CO NHCH₂— 105(R) H (4-methoxyphenyl) 3,4-methylenedioxyphenyl 4-methoxyphenyl 614.6COC₂H₄CONH CH₂— 106 (R) H 4-chlorophenyl 3,4-methylenedioxyphenyl4-methoxyphenyl 642.1 sulfonylaminocarbonyl aminomethyl 107 (R) H5-(acetyl)thien-2-yl 3,4-methylenedioxyphenyl 4-methoxyphenyl 576.6carbonylaminomethyl 108 (R) H pyridin-3-yl 3,4-methylenedioxyphenyl4-methoxyphenyl 529.5 carbonylaminomethyl 109 (R) H 2-[2-(methyl)butyl3,4-methylenedioxyphenyl 4-methoxyphenyl 536.6 aminocarbonyl]ethyl 110(R) H (3,4,5-trimethoxy 3,4-methylenedioxyphenyl 4-methoxyphenyl 646.7phenyl) C₂H₄CONHCH₂ 111 (R) H 3-methoxy 3,4-methylenedioxyphenyl4-methoxyphenyl 573.6 phenylamino carbonylaminomethyl 112 (R) H2-[(C₆H₅) 3,4-methylenedioxyphenyl 4-methoxyphenyl 570.6 CHCH₃NHCO]ethyl113 (R) H (phenoxy)CH 3,4-methylenedioxyphenyl 4-methoxyphenyl 586.6(CH₂CH₃)CON HCH₂— 114 (R) H (3-nitrophenyl) 3,4-methylenedioxyphenyl4-methoxyphenyl 623.6 CH₂SO₂NHCH₂ 115 (R) H 1-(ethoxycarbonyl)3,4-methylenedioxyphenyl 4-methoxyphenyl 636.7piperidin-4-yl-aminomethyl carbonylaminomethyl 116 (R) H 4-ethoxyphenyl3,4-methylenedioxyphenyl 4-methoxyphenyl 587.6 aminocarbonyl aminomethyl117 (R) H 2-chloropyridin- 3,4-methylenedioxyphenyl 4-methoxyphenyl564.0 5-ylcarbonyl aminomethyl 118 (R) H 2-[N,N-(ethylcyano)3,4-methylenedioxyphenyl 4-methoxyphenyl 609.7 (benzyl)aminocarbonyl]ethyl 119 (R) H 4-(methylthio) 3,4-methylenedioxyphenyl4-methoxyphenyl 589.7 phenylamino carbonylaminomethyl 120 (R) H2,4-difluorophenyl 3,4-methylenedioxyphenyl 4-methoxyphenyl 564.5carbonylaminomethyl 121 (R) H 2-propyl 3-(acetyl)indol-5-yl4-methoxyphenyl 474 122 (R) H 2-[4-(phenylcarbonyl)3,4-methylenedioxyphenyl 4-methoxyphenyl 639.7 piperazin-1-ylcarbonyl]ethyl 123 (R) H (4-hydroxyphenoxy)CH 3,4-methylenedioxyphenyl4-methoxyphenyl 588.6 (CH₃)CO NHCH₂— 124 (R) H 2-[4-(furan-2-ylcarbonyl)3,4-methylenedioxyphenyl 4-methoxyphenyl 629.7 piperidin-1-ylcarbonyl]ethyl 125 (R) H N-(3,5-(dimethoxy) 3,4-methylenedioxyphenyl4-methoxyphenyl 588.6 phenylcarbonyl) aminomethyl 126 (R) H 2-propyl3-(acetyl)indol-5-yl 2,3,6-trimethyl-4- 163-171 516 methoxyphenyl 127(R) H 2-propyl 3-(isobutyro) 2,3,6-trimethyl-4- 544 indol-5-ylmethoxyphenyl 128 (R) H methylsulfonyl 3,4-methylenedioxyphenyl2,6-dimethyl-4-  98-102 530 aminomethyl methoxyphenyl 129 (R) Hphenylsulfonyl 3,4-methylenedioxyphenyl 2,6-dimethyl-4- 103-107 592aminomethyl methoxyphenyl 130 (R) H acetylaminomethyl3,4-methylenedioxyphenyl 2,6-dimethyl-4- 494 methoxyphenyl 131 (R) Hmethoxycarbonyl 3,4-methylenedioxyphenyl 2,6-dimethyl-4- 510 aminomethylmethoxyphenyl 132 (R) H 4-carboxyphenyl 3,4-methylenedioxyphenyl2,6-dimethyl-4- 150-153 600 carbonylaminomethyl methoxyphenyl 133 (R) H4-methylbenzoate 3,4-methylenedioxyphenyl 2,6-dimethyl-4- 119-124 614carboxamidomethyl methoxyphenyl 134 (R) H (2-pyrrol-1-yl)3,4-methylenedioxyphenyl 2,6-dimethyl-4- 104-108 621 phenylcarbonylmethoxyphenyl 135 (R) H 4-(methoxy indol-5-yl 2,6-dimethyl-4- 122-127609 carbonyl)phenyl methoxyphenyl carbonylaminomethyl 136 (R) H1-hydroxyethyl benzimidazol-5-yl 2,3,6-trimethyl-4- 477 methoxyphenyl137 (R) H (imidazol-4-yl) 3,4-methylenedioxyphenyl 2,6-dimethyl-4- 503methyl methoxyphenyl 138 (R) H N-(phenyl 3,4-methylenedioxyphenyl2,6-dimethyl-4- 556 carbonyl)aminomethyl methoxyphenyl 139 (R) H2-chlorophenylmethoxy 3,4-methylenedioxyphenyl 4-methoxyphenyl 592carbonylaminomethyl 140 (R) H 3-nitrophenylmethoxy3,4-methylenedioxyphenyl 4-methoxyphenyl 603 carbonylaminomethyl 141 (R)H 3,5-dichlorophenyl- 3,4-methylenedioxyphenyl 4-methoxyphenyl 626methoxycarbonyl- aminomethyl 142 (R) H 2-propyl benzoxazol-5-yl4-methoxyphenyl 434 143 (R) H 2-(pyrrol-1-yl) 3,4-methylenedioxyphenyl2,6-dimethyl-4- 621 benzamidomethyl methoxyphenyl 144 (R) H1-hydroxyethyl 3,4-methylenedioxyphenyl 2,6-dimethyl-4- 467methoxyphenyl 145 (R) H 2-propyl indol-5-yl 2,5-dimethyl-4- 117-121 460methoxyphenyl 146 (R) H benzyloxy 3,4-methylenedioxyphenyl4-methoxyphenyl 558 carbonylaminomethyl 147 (R) H 4-methoxyaniline3,4-methylenedioxyphenyl 4-methoxyphenyl 573 carbonylaminomethyl 148 (R)H 4-nitrobenzyloxy 3,4-methylenedioxyphenyl 4-methoxyphenyl 603carbonylaminomethyl 149 (R) H 2-bromobenzyloxy 3,4-methylenedioxyphenyl4-methoxyphenyl 638 carbonylaminomethyl

II. Compounds of the Formula (Ia) and (Ib) wherein R is —CH(R²)Ar¹, Ar²is 2,3,6 trimethyl-4-methoxyphenyl or 2,6-dimethyl-4-methoxyphenyl, R²is hydrogen, and the other groups are defined as follows:

CPD # R¹ Ar¹ 1 N-[4-(methoxycarbonyl)phenyl- 3,4-methylene-carbonyl]aminomethyl dioxyphenyl 2 N-(benzyloxycarbonyl)aminopropyl3,4-methylene- dioxyphenyl 3 N-[2-(pyrrol-1-yl)phenylcarbonyl]3,4-methylene- aminomethyl dioxyphenyl 42-[(diphenyl)methylaminocarbonyl]ethyl 3,4-methylene- dioxyphenyl 5N-[3-(cyano)phenylaminocarbonyl] 3,4-methylene- aminomethyl dioxyphenyl6 N-(thien-2-ylcarbonyl)aminomethyl 3,4-methylene- dioxyphenyl 7N-(phenylcarbonyl)aminomethyl 3,4-methylene- dioxyphenyl 8(C₆H₅)CHCH₃NHCO(C₂H₄)CONHCH₂— 3,4-methylene- dioxyphenyl 9(4-methoxyphenyl)COC₂H₄CONHCH₂— 3,4-methylene- dioxyphenyl 10N-(4-chlorophenylsulfonylaminocarbonyl) 3,4-methylene- aminomethyldioxyphenyl 11 N-(5-(acetyl)thien-2-ylcarbonyl) 3,4-methylene-aminomethyl dioxyphenyl 12 N-(pyridin-3-ylcarbonyl)aminomethyl3,4-methylene- dioxyphenyl 13 2-[2-(methyl)butylaminocarbonyl]ethyl3,4-methylene- dioxyphenyl 14 (3,4,5-trimethoxyphenyl)C₂H₄CONHCH₂—3,4-methylene- dioxyphenyl 15 N-(3-(methoxy)phenylaminocarbonyl)3,4-methylene- aminomethyl dioxyphenyl 16 2-[(C₆H₅)CHCH₃NHCO]ethyl3,4-methylene- dioxyphenyl 17 (phenoxy)CH(CH₂CH₃)CONHCH₂— 3,4-methylene-dioxyphenyl 18 (3-nitrophenyl)CH₂SO₂NHCH₂— 3,4-methylene- dioxyphenyl 19N-[1-(ethoxycarbonyl)-piperidin-4-yl- 3,4-methylene-aminomethylcarbonyl)aminomethyl dioxyphenyl 20N-(4-(ethoxy)phenylaminocarbonyl) 3,4-methylene- aminomethyl dioxyphenyl21 N-(2-chloropyridin-5- 3,4-methylene- ylcarbonyl)aminomethyldioxyphenyl 22 2-[N,N-(ethylcyano)(benzyl)aminocarbonyl] 3,4-methylene-ethyl dioxyphenyl 23 N-(4-(methylthio)anilinocarbonyl) 3,4-methylene-aminomethyl dioxyphenyl 24 N-(2,4- 3,4-methylene-difluorophenylcarbonyl)aminomethyl dioxyphenyl 25 2-propyl(3-acetyl)indol-5-yl 26 2-[4-(phenylcarbonyl)piperazin-1- 3,4-methylene-ylcarbonyl]ethyl dioxyphenyl 27 (4-hydroxyphenoxy)CH(CH₃)CONHCH₂—3,4-methylene- dioxyphenyl 28 2-[4-(furan-2-ylcarbonyl)pipenidin-1-3,4-methylene- ylcarbonyl]ethyl dioxyphenyl 29N-(3,5-(dimethoxy)phenylcarbonyl) 3,4-methylene- aminomethyl dioxyphenyl30 N-(benzyloxycarbonyl)aminopropyl benzoxazol-6-yl 31N-(benzyloxycarbonyl)aminopropyl benzofuran-5-yl

PREFERRED EMBODIMENTS

While the broadest definition of this invention is set forth in theSummary of the Invention, certain compounds of Formula (Ia) wherein Z isNHOH are preferred.

In addition, compounds of Formula (Ia) where Ar² is at least tetra orpenta-substituted are surprisingly selective in inhibiting procollagenC-proteinase relative to other collagenases.

I. A preferred group of compounds is that wherein:

R is —CH(R²)Ar¹ wherein R²is hydrogen.

(a) Within this preferred group (I) a more preferred group of compoundsof that wherein:

Ar¹ is heteroaryl and Ar² is a phenyl ring of formula (a).

(i) Within this more preferred group (I)(a), an even more preferredgroup of compounds is that wherein:

R³ and R⁷ are, independently of each other, alkyl, alkylthio, or halo;

R⁴ is hydrogen, alkyl, or halo;

R⁵ is alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy,hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino,dialkylamino, or alkylsulfonyl; and

R⁶ is hydrogen.

Within these preferred, more preferred and even more preferred groups ofcompounds, a particularly preferred group of compounds is that wherein:

Ar¹ is a heteroaryl ring, preferably optionally substituted indolyl orimidazolyl, more preferably indol-5-yl, 1-methylindol-5-yl,3-acetylindol-5-yl, 3-propionylindol-5-yl,3-(2-methylpropionyl)indol-5-yl, imidazol-5-yl,2-methylbenzimidazol-5-yl, or benzimidazol-5-yl;

R³ and R⁷ are, independently of each other, alkyl or halo, morepreferably methyl, chloro, or bromo;

R⁴ is hydrogen or alkyl, preferably methyl; and

R⁵ is alkyl, alkoxy, or halo, preferably methyl, methoxy, chloro, orbromo.

Within these preferred, more preferred, and particularly preferredgroups of compounds, an even more particularly preferred group ofcompounds is that wherein:

R¹ is alkyl, aralkyl, heteroalkyl, or -(alkylene)-C(O)—X where X isalkyl, amino, monosubstituted amino, disubstituted amino, orheterocyclyl,

more preferably 2-propyl, hydroxymethyl, tert-butoxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl,methoxymethyl, or -(alkylene)-C(O)—X where X is 2- or4-pyridylmethylamino, 1-alkoxycarbonylpyridin-4-ylamino, optionallysubstituted benzylamino, 4-optionally substitutedbenzyloxycarbonylpiperazin-1-yl, 4-optionally substitutedphenylpiperazin-1-yl, 4-alkoxycarbonylpiperazin-1-yl, or 4-optionallysubstituted heteroarylpiperazin-1-yl,

most preferably 2-propyl, hydroxymethyl, tert-butoxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl,methoxymethyl, 2-(2- or 4-pyridylmethylamino-carbonyl)ethyl,2-(1-ethoxycarbonylpyridin-4-ylaminocarbonyl)-ethyl,2-(benzylaminocarbonyl)ethyl,2-(4-benzyloxycarbonylpiperizin-1-ylcarbonyl)-ethyl,2-(4-phenylpiperazin-1-ylcarbonyl)-ethyl,2-(4-methoxycarbonylpiperazin-1-ylcarbonyl)ethyl,2-(4-acetylpiperazin-1-yl-carbonyl)ethyl, or2-(4-pyridin-2-ylpiperazin-1-ylcarbonyl)ethyl.

Within these preferred, more preferred, and particularly preferredgroups of compounds, an alternative even more particularly preferredgroup of compounds is that wherein:

R¹ is heteroalkyl or -(alkylene)-C(O)—X where X is alkyl, amino,monosubstituted amino, disubstituted amino, or heterocyclyl,

more preferably, methylsulfonylaminomethyl, phenylsulfonylaminomethyl,(3-nitrophenyl)CH₂SO₂NHCH₂, methylcarbonylaminomethyl,4-(methoxycarbonyl)phenylcarbonylaminomethyl,2-(pyrrol-1-yl)phenylcarbonylaminomethyl,3-cyanophenylaminocarbonylaminomethyl, thien-2-ylcarbonylaminomethyl,phenylcarbonylaminomethyl, (C₆H₅)CHCH₃NHCO(C₂H₄)CONHCH₂,(4-methoxyphenyl)COC₂H₄CONHCH₂,4-chlorophenylsulfonylaminocarbonylaminomethyl,5-(acetyl)thien-2-ylcarbonylaminomethyl,pyridin-3-ylcarbonylaminomethyl, (3,4,5-trimethoxyphenyl)C₂H₄CONHCH₂,3-methoxyphenylaminocarbonylaminomethyl, (phenoxy)CH(CH₂CH₃)CONHCH₂,1-(ethoxycarbonyl)piperidin-4yl-aminomethylcarbonylaminomethyl,3-(benzyloxycarbonylamino)propyl,2-[(diphenyl)methylaminocarbonyl]ethyl,2-[2-(methyl)butylaminocarbonyl]ethyl, or 2-[(C₆H₅)CHCH₃NHCO]ethyl.

(ii) Within this more preferred group (I)(a), another even morepreferred group of compounds is that wherein:

R⁴ and R⁶ are hydrogen;

R³ and R⁷ are, independently of each other, alkyl, or halo; and

R⁵ is alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy,hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino,dialkylamino, or alkylsulfonyl.

Within these preferred, more preferred, and even more preferred groupsof compounds, a particularly preferred group of compounds is thatwherein:

Ar¹ is a heteroaryl ring, preferably optionally substituted indolyl orimidazolyl, more preferably indol-5-yl, 1-methylindol-5-yl,3-acetylindol-5-yl, 3-propionylindol-5-yl,3-(2-methylpropionyl)indol-5-yl, imidazol-5-yl,2-methylbenzimidazol-5-yl, or benzimidazol-5-yl;

R³ is alkyl, preferably methyl;

R⁵ is alkyl, alkoxy, or halo, preferably methyl, methoxy, chloro, orbromo; and

R⁷ is alkyl or halo, preferably methyl, chloro, or bromo.

Within these preferred, more preferred, and particularly preferred groupof compounds, an even more particularly preferred group of compounds isthat wherein:

R¹ is alkyl, aralkyl, heteroalkyl, or -(alkylene)-C(O)—X where X isalkyl, amino, monosubstituted amino, disubstituted amino, orheterocyclyl,

more preferably 2-propyl, hydroxymethyl, tert-butoxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl,methoxymethyl, or -(alkylene)-C(O)—X where X is 2- or4-pyridylmethylamino, 1-alkoxycarbonylpyridin-4-ylamino, optionallysubstituted benzylamino, 4-optionally substitutedbenzyloxycarbonylpiperazin-1-yl, 4-optionally substitutedphenylpiperazin-1-yl, 4-alkoxycarbonylpiperazin-1-yl, or 4-optionallysubstituted heteroarylpiperazin-1-yl,

most preferably 2-propyl, hydroxymethyl, tert-butoxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl,methoxymethyl, 2-(2- or 4-pyridylmethylaminocarbonyl)ethyl,2-(1-ethoxycarbonylpyridin-4-ylaminocarbonyl)ethyl,2-(benzylaminocarbonyl)ethyl,2-(4-benzyloxycarbonylpiperizin-1-ylcarbonyl)ethyl,2-(4-phenylpiperazin-1-ylcarbonyl)ethyl,2-(4-methoxycarbonylpiperazin-1-ylcarbonyl)ethyl,2-(4-acetylpiperazin-1-yl-carbonyl)ethyl, or2-(4-pyridin-2-ylpiperazin-1-ylcarbonyl)ethyl.

Within these preferred, more preferred, and particularly preferredgroups of compounds, an alternative even more particularly preferredgroup of compounds is that wherein:

R¹ is heteroalkyl or -(alkylene)-C(O)—X where X is alkyl, amino,monosubstituted amino, disubstituted amino, or heterocyclyl,

more preferably, methylsulfonylaminomethyl, phenylsulfonylaminomethyl,(3-nitrophenyl)CH₂SO₂NHCH₂, methylcarbonylaminomethyl,4-(methoxycarbonyl)phenylcarbonylaminomethyl,2-(pyrrol-1-yl)phenylcarbonylaminomethyl,3-cyanophenylaminocarbonylaminomethyl, thien-2-ylcarbonylaminomethyl,phenylcarbonylaminomethyl, (C₆H₅)CHCH₃NHCO(C₂H₄)CONHCH₂,(4-methoxyphenyl)COC₂H₄CONHCH₂,4-chlorophenylsulfonylaminocarbonylaminomethyl,5-(acetyl)thien-2-ylcarbonylaminomethyl,pyridin-3-ylcarbonylaminomethyl, (3,4,5-trimethoxyphenyl)C₂H₄CONHCH₂,3-methoxyphenylaminocarbonylaminomethyl, (phenoxy)CH(CH₂CH₃)CONHCH₂,1-(ethoxycarbonyl)piperidin-4-yl-aminomethylcarbonylaminomethyl,3-(benzyloxycarbonylamino)propyl,2-[(diphenyl)methylaminocarbonyl]ethyl,2-[2-(methyl)butylaminocarbonyl]ethyl, or 2-[(C₆H₅)CHCH₃NHCO]ethyl.

(b) Within this preferred group (I), another more preferred group ofcompounds is that wherein:

Ar¹ is aryl and Ar² is a phenyl ring of formula (a).

(i) Within this more preferred group (I)(b), an even more preferredgroup of compounds is that wherein:

R³ and R⁷ are, independently of each other, alkyl, alkylthio, or halo;

R⁴ is hydrogen, alkyl, or halo;

R⁵ is alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy,hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino,dialkylamino, or alkylsulfonyl; and

R⁶ is hydrogen.

Within these preferred, more preferred and even more preferred groups ofcompounds, a particularly preferred group of compounds is that wherein:

Ar¹ is a phenyl ring substituted with one or two substituents selectedfrom hydroxy, methylenedioxy, or methoxycarbonyl, more preferably,3,4-methylenedioxyphenyl, 3,4-dihydroxyphenyl, or4-methoxycarbonylphenyl;

R³ and R⁷ are, independently of each other, alkyl or halo, morepreferably methyl, chloro, or bromo;

R⁴ is alkyl, preferably methyl; and

R⁵ is alkyl, alkoxy, or halo, preferably methyl, methoxy, chloro, orbromo.

Within these preferred, more preferred, and particularly preferred groupof compounds, an even more particularly preferred group of compounds isthat wherein:

R¹ is alkyl, aralkyl, heteroalkyl, or -(alkylene)-C(O)—X where X isalkyl, amino, monosubstituted amino, disubstituted amino, orheterocyclyl,

more preferably 2-propyl, hydroxymethyl, tert-butoxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl,methoxymethyl, or -(alkylene)-C(O)—X where X is 2- or4-pyridylmethylamino, 1-alkoxycarbonylpyridin-4-ylamino, optionallysubstituted benzylamino, 4-optionally substitutedbenzyloxycarbonylpiperazin-1-yl, 4-optionally substitutedphenylpiperazin-1-yl, 4-alkoxycarbonylpiperazin-1-yl, or 4-optionallysubstituted heteroarylpiperazin-1-yl,

most preferably 2-propyl, hydroxymethyl, tert-butoxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl,methoxymethyl, 2-(2- or 4-pyridylmethylaminocarbonyl)ethyl,2-(1-ethoxycarbonylpyridin-4-ylaminocarbonyl)ethyl,2-(benzylaminocarbonyl)ethyl,2-(4-benzyloxycarbonylpiperazin-1-ylcarbonyl)ethyl,2-(4-phenylpiperazin-1-ylcarbonyl)ethyl,2-(4-methoxycarbonylpiperazin-1-ylcarbonyl)ethyl,2-(4-acetylpiperazin-1-yl-carbonyl)ethyl, or2-(4-pyridin-2-ylpiperazin-1-ylcarbonyl)ethyl.

Within these preferred, more preferred, and particularly preferredgroups of compounds, an alternative even more particularly preferredgroup of compounds is that wherein:

R¹ is heteroalkyl or -(alkylene)-C(O)—X where X is alkyl, amino,monosubstituted amino, disubstituted amino, or heterocyclyl,

more preferably, methylsulfonylaminomethyl, phenylsulfonylaminomethyl,(3-nitrophenyl)CH₂SO₂NHCH₂, methylcarbonylaminomethyl,4-(methoxycarbonyl)phenylcarbonylaminomethyl,2-(pyrrol-1-yl)phenylcarbonylaminomethyl,3-cyanophenylaminocarbonylaminomethyl, thien-2-ylcarbonylaminomethyl,phenylcarbonylaminomethyl, (C₆H₅)CHCH₃NHCO(C₂H₄)CONHCH₂,(4-methoxyphenyl)COC₂H₄CONHCH₂,4-chlorophenylsulfonylaminocarbonylaminomethyl,5-(acetyl)thien-2-ylcarbonylaminomethyl,pyridin-3-ylcarbonylaminomethyl, (3,4,5-trimethoxyphenyl)C₂H₄CONHCH₂,3-methoxyphenylaminocarbonylaminomethyl, (phenoxy)CH(CH₂CH₃)CONHCH₂,1-(ethoxycarbonyl)piperidin-4-yl-aminomethylcarbonylaminomethyl,3-(benzyloxycarbonylamino)propyl,2-[(diphenyl)methylaminocarbonyl]ethyl,2-[2-(methyl)butylaminocarbonyl]ethyl, or 2-[(C₆H₅)CHCH₃NHCO]ethyl.

(ii) Another even more preferred group of compounds in group (I)(b), isthat wherein:

R⁴ and R⁶ are hydrogen;

R³ and R⁷ are, independently of each other, alkyl, or halo; and

R⁵ is alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy,hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino,dialkylamino, or alkylsulfonyl.

Within these preferred, more preferred and even more preferred groups ofcompounds, a particularly preferred group of compounds is that wherein:

Ar¹ is a phenyl ring substituted with one or two substituents selectedfrom hydroxy, methylenedioxy, or methoxycarbonyl, more preferably,3,4-methylenedioxyphenyl, 3,4-dihydroxyphenyl, or4-methoxycarbonylphenyl;

R³ is alkyl, preferably methyl;

R⁵ is alkyl, alkoxy, or halo, preferably methyl, methoxy, chloro, orbromo; and

R⁷ is alkyl or halo, preferably methyl, chloro, or bromo.

Within these preferred, more preferred, and particularly preferred groupof compounds, an even more particularly preferred group of compounds isthat wherein:

R¹ is alkyl, hydroxyalkyl, aralkyl, heteroalkyl, or -(alkylene)-C(O)—Xwhere X is alkyl, amino, monosubstituted amino, disubstituted amino, orheterocyclyl,

more preferably 2-propyl, hydroxymethyl, tert-butoxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl,methoxymethyl, or -(alkylene)-C(O)—X where X is 2- or4-pyridylmethylamino, 1-alkoxycarbonylpyridin-4-ylamino, optionallysubstituted benzylamino, N-(optionally substituted carbonyl)methylamino,N-(optionally substituted amido)methylamino, 4-optionally substitutedbenzyloxycarbonylpiperazin-1-yl, 4-optionally substitutedphenylpiperazin-1-yl, 4-alkoxycarbonylpiperazin-1-yl, or 4-optionallysubstituted heteroarylpiperazin-1-yl, 4-methanesulfonyl-piperazin-1-yl,4-acetylpiperazin-1-yl, 4-optionally substituted phenoxypiperazin-1-yl,most preferably 2-propyl, hydroxymethyl, tert-butoxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl,methoxymethyl, 2-(2- or 4-pyridylmethylamino-carbonyl)ethyl,2-(1-ethoxycarbonylpyridin-4-ylaminocarbonyl)-ethyl,2-(benzylaminocarbonyl)ethyl,2-(4-benzyloxycarbonylpiperazin-1-ylcarbonyl)-ethyl,2-(4-phenylpiperazin-1-ylcarbonyl)-ethyl,2-(4-methoxycarbonylpiperazin-1-ylcarbonyl)ethyl,2-(4-acetylpiperazin-1-yl-carbonyl)ethyl, or2-(4-pyridin-2-ylpiperazin-1-ylcarbonyl)ethyl.

Within these preferred, more preferred, and particularly preferredgroups of compounds, an alternative even more particularly preferredgroup of compounds is that wherein:

R¹ is heteroalkyl or -(alkylene)-C(O)—X where X is alkyl, amino,monosubstituted amino, disubstituted amino, or heterocyclyl,

more preferably, methylsulfonylaminomethyl, phenylsulfonylaminomethyl,(3-nitrophenyl)CH₂SO₂NHCH₂, methylcarbonylaminomethyl,4-(methoxycarbonyl)phenylcarbonylaminomethyl,2-(pyrrol-1-yl)phenylcarbonylaminomethyl,3-cyanophenylaminocarbonylaminomethyl, thien-2-ylcarbonylaminomethyl,phenylcarbonylaminomethyl, (C₆H₅)CHCH₃NHCO(C₂H₄)CONHCH₂,(4-methoxyphenyl)COC₂H₄CONHCH₂,4-chlorophenylsulfonylaminocarbonylaminomethyl,5-(acetyl)thien-2-ylcarbonylaminomethyl,pyridin-3-ylcarbonylaminomethyl, (3,4,5-trimethoxyphenyl)C₂H₄CONHCH₂,3-methoxyphenylaminocarbonylaminomethyl, (phenoxy)CH(CH₂CH₃)CONHCH₂,1-(ethoxycarbonyl)piperidin-4-yl-aminomethylcarbonylaminomethyl,3-(benzyloxycarbonylamino)propyl,2-[(diphenyl)methylaminocarbonyl]ethyl,2-[2-(methyl)butylaminocarbonyl]ethyl, or 2-[(C₆H₅)CHCH₃NHCO]ethyl.

II. Another preferred group of compounds is that wherein:

R is —CH(R²)Ar¹ wherein R² is alkyl.

Within this group (II), a more preferred group of compounds is thatwherein:

(a) Ar¹ is a heteroaryl ring, preferably optionally substituted indolylor imidazolyl, more preferably indol-5-yl, 1-methylindol-5-yl,3-acetylindol-5-yl, 3-propionylindol-5-yl,3-(2-methylpropionyl)indol-5-yl, imidazol-5-yl,2-methylbenzimidazol-5-yl, benzimidazol-5-yl; and

Ar² is a phenyl ring of formula (a).

Another more preferred group of compounds is that wherein:

(b) Ar¹ is aryl, preferably a phenyl ring substituted with one or twosubstituents selected from hydroxy, methylenedioxy, or methoxycarbonyl,more preferably, 3,4-methylenedioxyphenyl, 3,4-dihydroxyphenyl, or4-methoxycarbonylphenyl; and

Ar² is a phenyl ring of formula (a).

Within the more preferred groups II (a) and (b), an even more preferredgroup of compounds is that wherein:

(i) R³ and R⁷ are, independently of each other, hydrogen, alkyl,alkylthio, or halo, preferably methyl, methylthio, chloro, or bromo,more preferably methyl, chloro, or bromo;

R⁴ is hydrogen, alkyl or halo, preferably methyl, chloro, or bromo;

R⁵ is alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy,hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino,dialkylamino, or alkylsulfonyl, preferably alkyl, alkoxy, or halo, morepreferably methyl, methoxy, chloro, or bromo; and

R⁶ is hydrogen.

(ii) Another even more preferred group of compounds within groups II(a)and (b) is that wherein:

R³ and R⁶ are hydrogen;

R⁴ and R⁷ are, independently of each other, alkyl, or halo, preferablymethyl, chloro, or bromo; and

R⁵ is alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy,hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino,dialkylamino, or alkylsulfonyl, preferably alkyl, alkoxy, or halo, morepreferably methyl, methoxy, chloro, or bromo.

(iii) Another even more preferred group of compounds within groups II(a)and (b) is that wherein:

R⁴ and R⁶ are hydrogen

R³ and R⁷ are, independently of each other, alkyl, or halo; and

R⁵ is alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy,hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino,dialkylamino, or alkylsulfonyl.

Within the above preferred, more preferred and an even more preferredgroups of (II)a and (II)b, a particularly preferred group of compoundsis that wherein:

R¹ is alkyl, aralkyl, heteroalkyl, or -(alkylene)-C(O)—X where X isalkyl, amino, monosubstituted amino, disubstituted amino, orheterocyclyl,

more preferably 2-propyl, hydroxymethyl, tert-butoxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl,methoxymethyl, or -(alkylene)-C(O)—X where X is 2- or4-pyridylmethylamino, 1-alkoxycarbonylpyridin-4-ylamino, optionallysubstituted benzylamino, 4-optionally substitutedbenzyloxycarbonylpiperazin-1-yl, 4-optionally substitutedphenylpiperazin-1-yl, 4-alkoxycarbonylpiperazin-1-yl, or 4-optionallysubstituted heteroarylpiperazin-1-yl,

most preferably 2-propyl, hydroxymethyl, tert-butoxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl,methoxymethyl, 2-(2- or 4-pyridylmethylaminocarbonyl)ethyl,2-(1-ethoxycarbonylpyridin-4-ylaminocarbonyl)ethyl,2-(benzylaminocarbonyl)ethyl,2-(4-benzyloxycarbonylpiperizin-1-ylcarbonyl)ethyl,2-(4-phenylpiperazin-1-ylcarbonyl)ethyl,2-(4-methoxycarbonylpiperazin-1-ylcarbonyl)ethyl,2-(4-acetylpiperazin-1-yl-carbonyl)ethyl, or2-(4-pyridin-2-ylpiperazin-1-ylcarbonyl)ethyl.

Within the above preferred, more preferred and even more preferredgroups of (II), an alternative particularly preferred group of compoundsis that wherein:

R¹ is heteroalkyl or -(alkylene)-C(O)—X where X is alkyl, amino,monosubstituted amino, disubstituted amino, or heterocyclyl,

more preferably, methylsulfonylaminomethyl, phenylsulfonylaminomethyl,(3-nitrophenyl) CH₂SO₂NHCH₂, methylcarbonylaminomethyl,4-(methoxycarbonyl)phenylcarbonylaminomethyl,2-(pyrrol-1-yl)phenylcarbonylaminomethyl,3-cyanophenylaminocarbonylaminomethyl, thien-2-ylcarbonylaminomethyl,phenylcarbonylaminomethyl, (C₆H₅)CHCH₃NHCO(C₂H₄)CONHCH₂,(4-methoxyphenyl)COC₂H₄CONHCH₂,4-chlorophenylsulfonylaminocarbonylaminomethyl,5-(acetyl)thien-2-ylcarbonylaminomethyl,pyridin-3-ylcarbonylaminomethyl, (3,4,5-trimethoxyphenyl)C₂H₄CONHCH₂,3-methoxyphenylaminocarbonylaminomethyl, (phenoxy)CH(CH₂CH₃)CONHCH₂,1-(ethoxycarbonyl)piperidin-4-yl-aminomethylcarbonylaminomethyl,3-(benzyloxycarbonylamino)propyl,2-[(diphenyl)methylaminocarbonyl]ethyl,2-[2-(methyl)butylaminocarbonyl]ethyl, or 2-[(C₆H₅)CHCH₃NHCO]ethyl.

III. A third preferred group of compounds is that wherein:

R is —CH(R²)Ar¹ wherein R² is hydrogen;

Ar¹ is heteroaryl; and

Ar² is a naphthyl ring of formula (b).

IV. A fourth preferred group of compounds is that wherein:

R is —CH(R²)Ar¹ wherein R² is hydrogen;

Ar¹ is aryl; and

Ar² is a naphthyl ring of formula (b).

V. A fifth preferred group of compounds is that wherein:

R is —CH(R²)CH═CHAr¹ wherein R² is hydrogen;

Ar¹ is heteroaryl; and

Ar² is a phenyl ring of formula (a) or a naphthyl ring of formula (b).

IV. A sixth preferred group of compounds is that wherein:

R is —CH(R²)CH═CHAr¹ wherein R² is hydrogen;

Ar¹ is aryl; and

Ar²is a phenyl ring of formula (a) or a naphthyl ring of formula (b).

Within the broadest definition of this invention set forth in theSummary of the Invention, certain compounds of Formula (I) wherein Z is—OH are preferred as intermediates in the synthesis of compounds whereinZ is —NHOH.

General Synthetic Scheme

Compounds of this invention can be made by the methods depicted in thereaction schemes shown below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA),Emka-Chemie, or Sigma (St. Louis, Mo., USA), Calbiochem-Novabiochem (SanDiego, Calif.) or Indofine Chemical Co. (Bellemead, N.J., USA) or areprepared by methods known to those skilled in the art followingprocedures set forth in references such as Fieser and Fieser's Reagentsfor Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991); Rodd'sChemistry of Carbon Compounds, Volumes 1-5 and Supplementals (ElsevierScience Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wileyand Sons, 1991), March's Advanced Organic Chemistry, (John Wiley andSons, 4th Edition), and Larock's Comprehensive Organic Transformations(VCH Publishers Inc., 1989). These schemes are merely illustrative ofsome methods by which the compounds of this invention can besynthesized, and various modifications to these schemes can be made andwill be suggested to one skilled in the art having referred to thisdisclosure.

The starting materials and the intermediates of the reaction may beisolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography, and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Preparation of Compounds of Formula (Ia) and (Ib)

Schemes A, B, and C describe alternative methods to generate thecompounds of Formulae (Ia) and (Ib).

A compound of Formula (Ia) or (Ib) wherein R is —CH(R²)Ar¹, R², and Ar²are as defined in the Summary of the Invention is prepared from asuitably N-protected α-amino 1 as shown in Scheme A.

Treatment of an α-aminoacetate of formula 1 (where R is an alkyl such asmethyl, ethyl, or tert-butyl or an aralkyl such as benzyl) with acompound of formula 2 where R² is hydrogen or alkyl under reductiveamination reaction conditions i.e., in the presence of a suitablereducing agent (e.g., sodium cyanoborohydride, sodiumtriacetoxyborohydride, and the like) and an organic acid (e.g., glacialacetic acid, trifluoroacetic acid, and the like) provides an N-alkylatedα-amino ester of formula 3. Suitable solvents for the reaction arehalogenated hydrocarbons (e.g., 1,2-dichloroethane, chloroform, and thelike).

Compounds of formula 1 are commercially available or they can beprepared by methods well known in the art. For example, esters ofnatural and unnatural amino acids such as D-valine benzyl esterp-tosylate salt, D-valine ethyl ester hydrochloride salt, D-valinetert-butyl ester hydrochloride salt, L-, D- or DL-serine methyl esterare commercially available. Alpha-thiomethyl amino acids can be preparedby following the procedures described in Arnold, L. D., Kalantar, T. H.,Vederas, J. C. J. Am. Chem. Soc., 107, 7108, (1985). Others can beprepared by esterification of N-protected α-amino acids (suitableamino-protecting group are tert-butoxycarbonyl, benzyloxycarbonyl, andthe like), followed by deprotection of the amino group as described inExample 1.

Sulfonylation of 3 with an arylsulfonyl chloride of formula 4 provides a2-(arylsulfonylamino)acetate of formula 5. The sulphonation reaction canbe carried out by methods well known in the art e.g., reacting 3 with acompound of formula 4 in the presence of trimethylsilylcyanide inacetonitrile. Compounds of formula 4 are commercially available or theycan be prepared by methods well known in the art. For example,4-methoxy-benzenesulfonyl chloride,4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride,4-chloro-2,5-dimethylbenzenesulfonyl chloride, 2-dibenzofuransulfonylchloride, 4-bromobenzenesulfonyl chloride, 2-naphthalenesulfonylchloride, and 1-naphthalenesulfonyl chloride are commercially available.Others can be prepared by the procedures described in Bosshard, E. H.et. al., Helv. Chim. Acta, 42, 1653, (1959); Colter, A. K. and Turkos,R. E. C., Canadian J. of Chem., 56, 585, (1978); Buchanan, G. W.,et.al., J. Org. Chem, 40, 2357-2359 (1975) and Fujino, M, et. al., Chem.Pharm. Bull., 10, 2825-2831 (1981). Typically, an unsulfonylated areneis treated with chlorosulfonic acid in dichloromethane at −5° C. to 10°C. to give the desired arenesulfonyl chloride.

Conversion of 5 to the corresponding carboxylic acid is dependent on thenature of the R group. For example, if R is a benzyl group then it isremoved under hydrogenation reaction conditions. If R is an alkyl groupsuch as methyl or ethyl group then it is removed under basic hydrolysisreaction conditions i.e., in the presence of an aqueous base (e.g.,sodium hydroxide, lithium hydroxide, and the like) in an alcoholicorganic solvent such as methanol, ethanol, and the like. If R is thetert-butyl group, then it is removed under acidic conditions.

Compound 6 can be converted to a compound of Formula (Ia) or (Ib) byconverting 6 to an acyl derivative of formula 7 where Y is a leavinggroup under acylating conditions (e.g., chloro, succinimido, and thelike). Treatment of 7 with N,O-bis-trimethylsilylhydroxylamine followedby acidic workup or upon the addition of methanol provides a compound ofFormula (Ia) or (Ib) directly.

The acyl derivative 7 can be prepared by methods known to those ofordinary skill in the art. For example, compound 7 where Y is chloro canbe prepared by reacting compound 5 with a chlorinating agent such asoxalyl chloride in a suitable organic solvent such as methylenechloride.

Alternatively, a compound of Formula (Ia) or (Ib) can be prepared from acompound of formula 6 via two steps by first reacting 6 with anO-substituted hydroxylamine (e.g., O-benzylhydroxylamine,O-tert-butylhydroxylamine, and the like) to give an O-protectedhydroxamate of formula 8. The reaction is carried out in the presence ofa coupling agent (e.g., N,N-dicyclohexylcarbodiimide,N-ethyl-N′-(3-dimethylamino-propyl)carbodiimide, and the like), anorganic base (e.g., dimethylamino-pyridine, triethylamine, pyridine,N-methylmorpholine, and the like) and optionally hydroxybenzotriazole.Suitable solvents for the reaction are methylene chloride,dichloroethane, dimethylformamide, and the like. Removal of theO-protecting group then provides a compound of Formula (Ia) or (Ib). Thereaction conditions utilized depend on the nature of the R′ group e.g.,if R′ is tert-butyl, then the reaction is carried out in an inertsolvent such as dichloromethane, in the presence of an acid (e.g., dryhydrogen chloride, trifluoroacetic acid, and the like). If R′ is benzyl,then hydrogenolysis conditions utilizing a metal catalyst such aspalladium in an inert solvent such as ethyl acetate or tetrahydrofuranare required. A compound of formula 5, 7, or 8 can also be converted toa compound of Formula (Ia) or (Ib) by the procedures described in PCTApplication, Publication No. 98/32748.

A compound of Formula (Ia) or (Ib) where R is —CH(R²)Ar¹ and othergroups are as defined in the Summary of the Invention can also beprepared from an α-amino acetate 1 as shown in Scheme B.

Sulfonylation of a compound of formula 1 with an arylsulfonyl chlorideunder the reaction conditions described in Scheme A above, provides2-arylsulfonylacetate of formula 9 which is converted to a compound offormula 5 either:

(a) by reacting compound 9 where with an alkylating agent of formulaAr¹CHR²X (where X is a leaving group such as chloro, bromo, mesylate,triflate, and the like under alkylating conditions) in the presence of abase (e.g., sodium carbonate, potassium carbonate, cesium carbonate, andthe like) and in a suitable solvents such as tetrahydrofuran, dioxane,N,N-dimethylformamide and the like; or

(b) by reacting compound 9 with an alcohol of formula Ar¹CHR²OH in thepresence of a trialkylphosphine or a triaryl phosphine, preferablytributylphosphine, triphenylphosphine, preferably tributylphosphine, anda dialkyl azodicarboxylate such as diethyl or diisopropylazodicarboxylate or (1,1′-azodicarbonyl)dipiperidine, preferably(1,1′-azo-dicarbonyl)dipiperidine. Suitable solvents include aromatichydrocarbons such as benzene, and the like.

Compound 5 is then converted to a compound of Formula (Ia) or (Ib) asdescribed in Scheme A above.

A compound of Formula (Ia) or (Ib) where R is —CH(R²)Ar¹ and othergroups are as defined in the Summary of the Invention can also beprepared from an α-aminoacid 11 as shown in Scheme C.

Sulfonylation of an α-amino acid 11 with an arylsulfonyl chloride offormula 4 in the presence of a base such as triethylamine provide2-arylsulfonylamino acetic acid of formula 12. The reaction is carriedout in an organic solvent and water mixture such as tetrahydrofuran andwater. Compound 12 can be converted to a compound of Formula (Ia) or(Ib) by method (a) or (b).

In method (a), esterification of 12 provides a compound of formula 9(where R is alkyl such as methyl, tert-butyl or aralkyl such as benzyl)which is then converted to a compound of Formula (Ia) or (Ib) byproceeding as described in Schemes A and B above.

In method (b), compound 12 is reacted with an N,O-protectedhydroxylamine, such asO-(2,4-dimethoxy-benzyl)-N-(2,4,6-trimethoxybenzyl)hydroxylamine, underthe conditions described in Barlaam, B., et al., Tet. Lett., Vol. 39,7865, (1998) to give a compound of formula 13. Alkylation of 13 providesa compound of formula 14 which upon treatment with trifluoroacetic acidin methylene chloride in the presence of triethylsilane provides acompound of Formula (Ia) or (Ib) ((see., Barlaam, B., et al., Tet.Lett., Vol. 39, 7865, (1998)).

A compound of Formula (Ia) or (Ib) where R is —CH(R²)CH═CHAr¹ and othergroups are as defined in the Summary of the Invention can also beprepared from an α-amino acetate 1 as shown in Scheme D.

A compound of Formula (Ia) or (Ib) were R is —CH(R²)CH═CHAr¹ is preparedby alkylating a compound of formula 9 (R cannot be benzyl) with analkylating agent of formula 15 where X is a leaving group underalkylating conditions (e.g., chloro, bromo, mesylate, triflate, and thelike) in the presence of a base (e.g., sodium carbonate, potassiumcarbonate, cesium carbonate, and the like) and in a suitable solventssuch as tetrahydrofuran, dioxane, N,N-dimethylformamide and the like, togive a compound of formula 16. Hydrolysis of the ester group in 16 givesthe corresponding acid which is then converted to a compound of Formula(Ia) or (Ib) by preparing the acid chloride derivative followed bytreatment with N,O-bis-trimethylsilylhydroxylamine as described inScheme A above.

A compound of formula 15 such as cinnamyl chloride is commerciallyavailable.

A compound of Formula (Ia) or (Ib) wherein Ar² is as defined in theSummary of the Invention, R is CH₂Ar¹ (wherein Ar¹ is3,4-methylenedioxyphenyl), and R¹ is —CH₂NHCOOR″ (wherein R″ ishydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, or heterocyclylalkyl) can be prepared fromN-protected diaminopropionic acid 2, as shown in Scheme E and asdescribed more fully in Example 16.

A compound of Formula (Ia) or (Ib) wherein Ar² is as defined in theSummary of the Invention, R is CH₂Ar¹ (wherein Ar¹ is3,4-methylenedioxyphenyl), and R¹ is —CH₂NHCONHAr can be prepared fromthe resin of formula 7 (of Scheme E) as shown in Scheme F and asdescribed more fully in Example 17.

Utility, Testing, and Administration Utility

Compounds of this invention are useful in the treatment of diseasesassociated with excessive deposition of interstitial collagens,exemplified by interstitial pulmonary fibrosis, pericentral fibrosis,Symmers' fibrosis, perimuscular fibrosis, kidney and liver fibrosis,idiopathic pulmonary fibrosis, endocardial sclerosis, hepatitis, acuterespiratory distress syndrome, arthritis, cystic fibrosis, tendonsurgery, surgical adhesions, corneal scarring, and restenosis.

Compounds of this invention are inhibitors of procollagen C-proteinase.Therefore, they inhibit C-terminal processing of types I, II, and IIIcollagens necessary for their ability to form insoluble collagenfibrils. Furthermore, selected compounds of the invention selectivelyinhibit procollagen C-proteinase over other collagen degradating enzymessuch as collagenase-1, collagenase-2, and collagenase-3. Therefore, thenatural resorption of collagen mediated by collagenase-1, collagenase-2and collagenase-3 is largely unaffected resulting in compounds ofgreater therapeutic efficacy. In particular, preferred compounds of thisinvention inhibit procollagen C-proteinase with greater than 100 foldselectivity over collagenase-1, collagenase-2, and collagenase-3.Selective inhibition of procollagen C-proteinase over collagenase-1,collagenase-2, and collagenase-3 was demonstrated by the assaysdescribed in the Examples. Thereby, this invention allows the treatmentof fibrotic diseases by administering to a patient an agent thatselectively inhibits procollagen C-proteinase over collagenase-1collagenase-2, and collagenase-3.

Testing

The ability of the compounds of Formulae (Ia) and (Ib) to inhibitprocollagen C-proteinase activity, may be demonstrated by a variety ofin vitro assays known to those of ordinary skill in the art, such as theassay described in Example 21. The selectivity against collagenaseenzymes may be determined by the assay described in Example 22.

The in vivo efficacy of compounds of Formulae (Ia) and (Ib) againstfibrotic disease and the deposition of collagen may be shown by numerousanimal models including the mouse bleomycin induced pulmonary fibrosismodel ((Phan, S. H., et.al. “Bleomycin-induced Pulmonary Fibrosis,” Am.Rev. Respir. Dis., 124:428-434 (1981) and Piguet, P. F., et al.“Effective Treatment of the Pulmonary Fibrosis Elicited in Mice byBleomycin or Silica with anti-CD-11 Antibodies,” Am. Rev. Resp. Dis.,147:435-441 (1993)), the sponge implant model ((Unemori, E. N., et al.“Human Relaxin Decreases Collagen Accumulation In Vivo in Two RodentModels of Fibrosis,” J. Invest. Dermatol, 101:280-285 (1993)), thecarbon tetrachloride or NDMU induced renal fibrosis model, as well asother animal models cited in WO 97/05865 (“C-Proteinase Inhibitors forthe Treatment of Disorders Relating to the Overproduction of Collagen”),published 20 Feb. 1997.

Administration and Pharmaceutical Composition

In general, the compounds of this invention will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. The actualamount of the compound of this invention, i.e., the active ingredient,will depend upon numerous factors such as the severity of the disease tobe treated, the age and relative health of the subject, the potency ofthe compound used, the route and form of administration, and otherfactors. The drug can be administered more than once a day, preferablyonce or twice a day.

Therapeutically effective amounts of compounds of Formula (Ia) or (Ib)may range from approximately 0.05-50 mg per kilogram body weight of therecipient per day; preferably about 0.3-20 mg/kg/day. Thus, foradministration to a 70 kg person, the dosage range would most preferablybe about 21 mg to 1.4 g per day.

In general, compounds of this invention will be administered aspharmaceutical compositions by any one of the following routes: oral,systemic (e.g., transdermal, intranasal or by suppository), orparenteral (e.g., intramuscular, intravenous or subcutaneous)administration. The preferred manner of administration is systemic usinga convenient daily dosage regimen which can be adjusted according to thedegree of affliction.

Intranasal delivery is typically accomplished with dry powderformulations, liquid solutions or suspensions suitable for nebulizationor with aerosol propellants suitable for use in a metered dose inhaler.Alternatively, drug substance may be associated with microspheres madeof materials such as gelatin, dextran, collagen or albumin Themicrospheres are conveniently delivered in freeze dried form with anasal insufflator device or a pressurized aerosol cannister. Penetrationenhancers such as amphiphilic steroids may also be used as additives toincrease the systemic absorption of the drug into the tissue.

Effective administration may also be accomplished by pulmonary orrespiratory delivery since polypeptides are readily absorbed through thecellular lining of the alveolar region of the mammalian lung.Advantageously, such administration frequently does not require the useof penetration enhancers as additives. Devices and methods for pulmonarydelivery deep into the lung are described in U.S. Pat. No. 5,780,014,issued Jul. 14, 1998 and U.S. Pat. No. 5,814,607, issued Sep. 29, 1998.

Lastly, compounds may be systemically administered by transdermaldelivery, which typically involves placing the drug on the surface ofthe skin and allowing it to permeate through the skin. Transdermaldelivery devices employ a structure such as an adhesive patch or thelike that serves as a reservoir for the drug and brings the drug intodiffusive contact with the skin. In one general typ, the structure is athree dimensionally stable matrix known as a monolithic matrix. Suchmatrices are described in more detail in U.S. Pat. Nos. 5,804,214,5,149,538 and 4,956,171 which describe matrices made of polymers andcopolymers of acrylic latexes, acrylic esters, methacrylic esters andvinyl acetates.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills or capsules are preferred) and thebioavailability of the drug substance. Recently, pharmaceuticalformulations have been developed especially for drugs that show poorbioavailability based upon the principle that bioavailability can beincreased by increasing the surface area i.e., decreasing particle size.For example, U.S. Pat. No. 4,107,288 describes a pharmaceuticalformulation having particles in the size range from 10 to 1,000 nm inwhich the active material is supported on a crosslinked matrix ofmacromolecules. U.S. Pat. No. 5,145,684 describes the production of apharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 nm) in the presence of asurface modifier and then dispersed in a liquid medium to give apharmaceutical formulation that exhibits remarkably highbioavailability.

The compositions are comprised of in general, a compound of Formula (Ia)or (Ib) in combination with at least one pharmaceutically acceptableexcipient. Acceptable excipients are non-toxic, aid administration, anddo not adversely affect the therapeutic benefit of the compound ofFormula (Ia) or (Ib). Such excipient may be any solid, liquid,semi-solid or, in the case of an aerosol composition, gaseous excipientthat is generally available to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Other suitable pharmaceutical excipients and their formulations aredescribed in Remington's Pharmaceutical Sciences, edited by E. W. Martin(Mack Publishing Company, 18th ed., 1990).

The amount of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationwill contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt% of a compound of formula I based on the total formulation, with thebalance being one or more suitable pharmaceutical excipients.Preferably, the compound is present at a level of about 1-80 wt %.Representative pharmaceutical formulations containing a compound ofFormula (Ia) or (Ib) are described in Example 18.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Example 1N-hydroxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzene-sulfonyl)amino]-3-methylbutyramide(Table I, Cmpd 12)

Step 1

N-Tert-butoxycarbonyl-D-valine (70 g, 0.32 mol) and cesium carbonate(200.2 g, 0.615 mol) were stirred in dry dimethylformamide (550 mL).Benzyl bromide (40.32 mL, 0.336 mol) was added and the reaction mixturewas stirred overnight. The material was concentrated on theroto-evaporator and the residue was dissolved in methylene chloride (200mL) and the methylene chloride layer was washed with water and brine,dried over magnesium sulfate and concentrated to giveN-tert-butoxycarbonyl-D-valine benzyl ester (97 g) as a viscous oil.

Step 2

N-Tert-butoxycarbonyl-D-valine benzyl ester (70.7 g, 0.23 mol) wasdissolved in a mixture of trifluoroacetic acid and methylene chloride(150 mL in 1:4 ratio) and the reaction mixture was heated at 50-60° C.After 6 h, the reaction mixture was concentrated to give D-valine benzylester trifluoroacetic acid salt (156.8 g) as a viscous oil which wasconverted to the free amine just prior to use.

Step 3

1 N Sodium hydroxide (80 mL) was added to a solution of D-valine benzylester trifluoroacetic acid salt (10 g, 31.1 mmol) in methylene chloride(80 mL) and the reaction mixture was stirred until all the startingmaterial was converted to the free amine. The organic phase wascollected and washed with brine, dried over magnesium sulfate, andconcentrated to give D-valine benzyl ester (5.35 g) as a clear oil.

Step 4

To a solution of D-valine benzyl ester (4 g, 19.3 mmol) andtrimethylsilylcyanide (7.2 mL, 57.9 mmol) in acetonitrile (40 mL) wasadded 4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride (4.8 g, 19.3mmol). After 3 h, the reaction mixture was diluted with ethyl acetate(100 mL) and transferred to a separatory funnel. Aqueous hydrochloricacid (120 mL, 2.5%) was added and the organic layer was separated andwashed with 5% sodium bicarbonate and brine and then dried overmagnesium sulfate. The organics were removed in vacuo to give2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3-methylbutyricacid benzyl ester (8 g) as a brown oil.

Step 5

To a mixture of2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3-methylbutyricacid benzyl ester (4.5 g, 10.72 mmol),3,4-(methylenedioxy)phenylmethanol (2.04 g, 13.41 mmol), andtributylphosphine (3.35 mL, 13.4 mmol) in dry benzene (60 mL) cooled inan ice bath was added 1,1′-(azodicarbonyl)dipiperidine (3.38 g, 13.4mmol). The reaction mixture was stirred overnight to room temperatureand then flash chromatographed on a silica gel column (5-10% ethylacetate/hexanes) to give2(R)-[(3,4-methylenedioxy-benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyricacid benzyl ester (4.8 g) as a white solid.

Step 6

To a solution of2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyricacid benzyl ester (4.7 g, 8.49 mmol) in a 4:1 mixture ofethanol/tetrahydrofuran (40 mL) was added 10% Pd/C (0.15 g). Thereaction mixture was placed under a hydrogen balloon. After 3 h, thereaction mixture was filtered through Celite and the Celite cake waswashed with ethanol. The filtrate was concentrated to give of2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyricacid (3.9 g) as a white foam.

Step 7

To a solution of2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)amino]-3-methylbutyricacid (3.82 g, 8.24 mmol) in dry methylene chloride (20 mL) was addedoxalyl chloride (2.2 mL, 24.72 mmol) and a drop of dimethylformamide.The reaction mixture was stirred for 4 h and then concentrated. Theresidue was dissolved in methylene chloride (20 mL) andN,O-bis-trimethylsilylhydroxylamine (8.8 mL, 41.2 mmol) was added. After4 h, methanol (1 mL) was added and the stirring was continued for 30min. Silica gel (10 g) was added and the material was concentrated todryness. The resultant powder was flash chromatographed on a silica gelcolumn and eluted with 50% ethyl acetate/hexanes to giveN-hydroxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyramide(2.46 g).

Example 2N-Hydroxy-2(R)-[(4-methoxycarbonylbenzyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyramide(Table I, Cmpd 21)

Step 1

To an ice-cooled solution of D-valine (50.5 g, 0.43 mol) andtriethylamine (145 mL, 1.034 mol) in a 1:1 mixture of tetrahydrofuranand water (350 mL) was added 4-methoxybenzenesulfonyl chloride (88.2 g,0.43 mmol). The reaction mixture was stirred and allowed to warm to roomtemperature overnight. The volatile organics were removed and theaqueous phase was extracted with diethyl ether. The aqueous phase wasacidified to pH 3 with 10% hydrochloric acid and the product wasextracted into ethyl acetate. The ethyl acetate layer was washed withbrine, dried over magnesium sulfate, and then concentrated to give2(R)-(4-methoxy-benzenesulfonylamino)-3-methylbutyric acid as a whitesolid (90.45 g).

Step 2

To a solution of 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyricacid (40 g, 139.2 mmol) and cesium carbonate (85.7 g, 444 mmol) indimethylformamide was added benzyl bromide (16.1 g, 135 mmol). Thereaction mixture was stirred overnight. The dimethylformamide wasremoved on the rotoevaporator and the residue was dissolved in ethylacetate (200 ml) and partitioned with an equal volume of water. Theorganic phase was collected and washed with an equal volume of brine.The aqueous phases were back extracted with ethyl acetate (2×150 ml),combined and dried over magnesium sulfate and condensed to provide2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid benzyl ester(42.6 g) as a white crystalline solid.

Step 3

To a solution of 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyricacid benzyl ester (1 g, 2.65 mmol) and 4-carboxymethylbenzyl bromide(0.577 g, 2.52 mmol) in dry dimethylformamide (60 mL) was addedpotassium carbonate (0.55 g, 4 mmol). The reaction mixture was stirredovernight and then condensed on the rotoevaporator. Purification byflash chromatography on a silica gel column using (5%) ethylacetate/hexanes as the eluant gave2(R)-[(4-methoxycarbonylbenzyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyricacid benzyl ester (0.965 g) which was converted toN-hydroxy-2(R)-[(4-methoxycarbonylbenzyl)-(4-methoxybenzene-sulfonyl)amino]-3-methylbutyramideby following Steps 6 and 7 in Example 1, above.

Example 3N-Hydroxy-2(R)-[(1H-indol-5-ylmethyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyramide(Table I, Cmpd 3)

Step 1

To a solution of 5-indole carboxylic acid (5.08 g, 31.5 mmol) in a 1:1mixture of methanol/methylene chloride (40 mL) was added(trimethylsilyl)diazomethane (33 mL, 2 M solution in hexanes) inportions over 15 min. The yellow colored solution was concentrated onthe rotoevaporator to provide methyl-5-indole carboxylate as a whitepowder (5.5 g).

Step 2

To a solution of methyl-5-indole carboxylate (4.9 g, 27.97 mmol) in dryacetonitrile (45 mL) was added di-tert-butyl dicarbonate (6.41 g, 29.36mmol) followed by 4-dimethylamino-pyridine (142 mg, 1.43 mmol). Thereaction mixture was stirred for 3 h and then loaded onto a flash silicagel column and eluted with ethyl acetate/hexane (5%) to give methyl(N-tert-butoxycarbonyl)indole-5-carboxylate as a clear viscous oil (7.69g).

Step 3

To a cooled solution (−78° C.) of methyl(N-tert-butoxycarbonyl)indole-5-carboxylate (7.6 g, 27.9 mmol) in drytetrahydrofuran (75 mL) was added diisobutylaluminum hydride (57 mL, 1.5M in toluene) via syringe over 5 min. After 1.5 h, the reaction mixturewas quenched by careful addition of methanol (15 mL) and allowed to warmto room temperature over 45 min. Water (20 mL) and a saturated solutionof ammonium chloride(10 mL) was added with vigorous stirring and theresultant inorganic precipitate was removed by filtration. The filtratewas condensed on the roto-evaporator and the residue was partitionedbetween a 1:1 mixture of ethyl acetate/water (160 mL). The ethyl acetatephase was washed with brine and the aqueous phases back extracted withethyl acetate. The organic phase was combined, dried with magnesiumsulfate, filtered and concentrated to provide(N-tert-butoxycarbonyl)indole-5-methanol (7.35 g) as a semi-viscousyellow oil which was used in the next step without further purification.

Step 4

To an ice-cooled mixture of2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid benzyl ester(5 g, 13.25 mmol) [prepared as described in Example 2 above],N-tert-butoxycarbonyl-5-indole methanol (3.8 g, 14.6 mmol) andtributylphosphine (3.6 mL, 14.6 mmol) in dry benzene (60 mL) was added[1,1′-azodicarbonyl]dipiperidine (3.68 g, 14.6 mmol). The reactionmixture was stirred overnight at room temperature and thenchromatographed on a silica gel column eluting with (5-10%) ethylacetate/hexanes to give of2(R)-[(N-tert-butoxy-carbonylindol-5-ylmethyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyricacid benzyl ester (6.5 g) as a white foamy semi-solid.

Step 5

A solution of2(R)-[(N-tert-butoxycarbonylindol-5-ylmethyl)-(4-methoxybenzene-sulfonyl)amino]-3-methylbutyricacid benzyl ester (2.7 g. 4.45 mmol) and trifluoroacetic acid (5 mL) inmethylene chloride (15 mL) was stirred for 2 h at room temperature. Theorganics were removed under vacuum and the residue was dissolved inethyl acetate (80 mL) and the ethyl acetate layer was washed with 5%sodium bicarbonate and brine. The organic layer was dried over magnesiumsulfate and concentrated to give a white foamy solid which waschromatographed on a silica gel column eluting with (5-100%) ethylacetate/hexanes. This procedure gave2(R)-[(1H-indol-5-yl-methyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyricacid benzyl ester (1.7 g) as a white foamy semi-solid, which wasconverted to2(R)-[(1H-indol-5-ylmethyl)-(4-methoxy-benzenesulfonyl)amino]-3-methylbutyricacid by following the procedure described in Example 1, Step 6 above.

Step 6

To an ice-cooled solution of2(R)-[(1H-indol-5-ylmethyl)-(4-methoxybenzene-sulfonyl)amino]-3-methylbutyricacid (0.32 g, 0.77 mmol), O-benzylhydroxyl amine (0.35 mL, 2.3 mmol),1-hydroxybenzotriazole hydrate (0.118 g, 0.77 mmol), andN-methyl-morpholine (0.12 mL, 1.1 mmol) in anhydrous dimethylformamidewas added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloridesalt (0.221 g, 1.2 mmol). The reaction mixture was stirred overnight andthen concentrated. The residue was dissolved in ethyl acetate (80 mL)and washed with 1.5% hydrochloric acid, 5% sodium bicarbonate, andbrine. Crystallization from hot CH₂Cl₂-hexanes of the residue followedby purification of the mother liquor by preparatory thin layerchromatography using 5% methanol/methylene chloride as the eluant gave2(R)-N-benzyloxy-[(1H-indol-5-ylmethyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyramide(0.31 g) as a tan crystalline powder.

Step 7

To a solution of2(R)-N-benzyloxy-[(1H-indol-5-ylmethyl)-(4-methoxybenzene-sulfonyl)amino]-3-methylbutyramide(0.34 g, 0.58 mmol) in a 1:1 mixture of ethanol/tetrahydrofuran (15 mL)was added 10% Pd/C (0.075 g). The reaction mixture was placed underhydrogen balloon. After 2.5 h, the reaction mixture was filtered througha pad of Celite (3.0 g) and the Celite pad was washed with ethanol (200mL). The filtrate was concentrated to give a tan semi-solid.Purification with preparative thin layer chromatography (7%methanol/methylene chloride) gaveN-hydroxy-2(R)-[(1H-indol-5-ylmethyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyramide(200 mg) as a tan solid.

Example 4N-Hydroxy-2(R)-[(3-nitro-4-methylbenzyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyramide(Table I, Cmpd 23)

Step 1

To an ice-cooled solution of2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid (30 g, 104.4mmol), [prepared as described in Example 2, step 1 above], in methylenechloride was added N,N′-diisopropyl-O-tert-butylisourea [can be preparedby the procedure described in Lon J. Mathias, Synthesis, 561-576,(1979)] (75 mL, 3.5 M solution) via additional funnel over 45 min. Thereaction mixture was maintained at 0° C. for 2 h, and then allowed towarm to room temperature overnight. Purification by flash chromatographyon a silica gel column using (10-20%) ethyl acetate/hexanes as theeluant gave of 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acidtert-butyl ester (18 g) as a white crystalline solid.

Step 2

To a solution of 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyricacid tert-butyl ester (0.15 g, 0.44 mmol) and potassium carbonate (0.32g, 2.32 mmol) in dry dimethylformamide (15 mL) was added3-nitro-4-methylbenzyl chloride (81.1 mg. 0.44 mmol). The reactionmixture was stirred overnight and then concentrated on therotoevaporator. The residue was dissolved in a 1:1 ethyl acetate andbrine (50 mL). The organic phase was isolated, dried over magnesiumsulfate, and concentrated to give2(R)-[(3-nitro-4-methylbenzyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyricacid tert-butyl ester (0.196 g) as a yellow viscous oil which wasconverted to2(R)-[(3-nitro-4-methylbenzyl)-(4-methoxy-benzenesulfonyl)amino]-3-methylbutyricacid by following the procedure described in Example 10, Step 8 below.2(R)-[(3-nitro-4-methylbenzyl)-(4-methoxybenzenesulfonyl)-amino]-3-methylbutyricacid is then converted toN-hydroxy-2(R)-[(3-nitro-4-methylbenzyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyramideby following Example 1, Steps 6 and 7 above.

Example 5N-hydroxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-hydroxypropionamide(Table I, Cmpd 5)

Step 1

To a suspension of D-serine (6.95 g, 66.1 mmol) in acetonitrile (100 mL)was added trimethylsilyl cyanide (40 mL, 298 mmol) and the resultingsolution was heated to 80° C. After 1 h,4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride (17.3 g, 69.4 mmol)was added and the heating was continued. After 12 h, the reactionmixture was cooled to room temperature. Methanol (15 mL) was added, andthe organics were removed in vacuo. The residue was diluted with diethylether (300 mL) and after cooling the reaction mixture to 0° C., the pHwas adjusted to 8 with 6 N aqueous sodium hydroxide solution. Theorganic layer was collected and the aqueous layer was extracted withdiethyl ether. The aqueous layer was adjusted to pH 4 and againextracted with ethyl acetate. The combined organic extracts were driedover magnesium sulfate and concentrated to afford2(R)-(4-methoxy-2,3,6-trimethylbenzene-sulfonylamino)-3-hydroxypropionicacid (20.5 g) as a brown foam which was used without furtherpurification.

Step 2

To a solution of2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3-hydroxypropionicacid (27.9 g, 87.9 mmol) in dimethylformamide (280 mL) at 0° C., wasadded potassium carbonate (72.9 g, 527 mmol) and a solution of3,4-methylenedioxybenzyl chloride ((60 g, 170.8 mmol, 50% (w/w)) inmethylene chloride. After 2 h, lithium iodide (5.88 g, 44 mmol) wasadded and the reaction mixture was warmed to rt. over 2 h. After 6 h,the reaction mixture was partitioned between ethyl acetate (600 mL) andwater (250 mL). The organic layer was separated, dried over magnesiumsulfate and concentrated in vacuo. The crude residue was chromatographed(300 g SiO₂, 15% ethyl acetate-hexanes) to afford2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3-hydroxypropionicacid 3,4-methylenedioxybenzyl ester (38.4 g) which was taken directlyinto the next reaction without further purification.

Step 3

2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3-hydroxypropionicacid 3,4-methylenedioxybenzyl ester (38.4 g) was dissolved in methylenechloride (140 mL) and dihydropyran (23 mL). The reaction mixture wascooled to 0° C. and p-toluenesulfonic acid monohydrate (0.78 g) wasadded. After 1 h, the reaction mixture was poured into saturated aqueoussodium bicarbonate (200 mL). The organic layer was separated, dried overmagnesium sulfate, and concentrated in vacuo. This residue waschromatographed (300 g SiO₂, 15% ethyl acetate-hexanes) to afford2(R)-(4-methoxy-2,6-dimethylbenzenesulfonyl-amino)-3-(tetrahydropyran-2-yloxy)propionicacid 3,4-methylenedioxybenzyl ester (41.4 g).

Step 4

To a solution of2(R)-(4-methoxy-2,6-dimethylbenzenesulfonyl-amino)-3-(tetrahydropyran-2-yloxy)propionicacid 3,4-methylenedioxybenzyl ester (9.0 g, 16.8 mmol) in benzene (150mL) at 0° C. was added 3,4-methylenedioxyphenyl methanol (3.8 g, 25.2mmol), tri-n-butylphosphine (5.1 g, 25.2 mmol), followed by1,1′-[azodicarbonyl]dipiperidine (6.35 g, 25.2 mmol). The reactionmixture was allowed to warm to room temperature over 4 h. After 16 h,the reaction mixture was diluted with an equal volume of hexanes, cooledto 0° C. for 2 h and filtered. The residue was chromatographed (300 gSiO₂, 15% ethyl acetate-hexanes) to afford2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-(tetrahydropyran-2-yloxy)propionicacid 3,4-methylenedioxybenzyl ester (10.0 g) as a pale orange oil.

Step 5

To a solution of2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzene-sulfonyl)amino]-3-(tetrahydropyran-2-yloxy)propionicacid 3,4-methylenedioxybenzyl ester (3.26 g, 4.57 mmol) in argondeoxygenated 80% ethanol-tetrahydrofuran (100 mL) was added 10% Pd-C (2g) and the resulting reaction mixture was hydrogenated at atmosphericpressure for 45 min. The reaction mixture was degassed under argon, theslurry was filtered over Celite, and the Celite pad was washed withample 80% ethanol-methylene chloride. The filtrate was concentrated andazeotroped with tetrahydrofuran (200 mL) and the residue was dissolvedin dimethylformamide (25 mL). O-Benzyl hydroxylamine (1.78 g,14.5 mmol),HOBT (0.71 g, 5.2 mmol), and EDAC (2.75 g) were added and the reactionmixture was stirred for 16 h. The reaction mixture was diluted withethyl acetate and was washed with 2.4 N aqueous hydrochloric acid andsaturated aqueous sodium bicarbonate. The mixture was then dried overmagnesium sulfate and concentrated in vacuo to afford crudeN-benzyloxy-2(R)-[(3,4-methylenedioxy-benzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-(tetrahydropyran-2-yloxy)-propionamide(2.8 g,) which was taken directly into the next reaction without furtherpurification.

Step 6

To a solution ofN-benzyloxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-(tetrahydropyran-2-yloxy)propionamide(1.7 g, 4.3 mmol) in methanol (100 mL) at 0° C. was addedp-toluenesulfonic acid monohydrate (150 mg). After 12 h, the reactionmixture was warmed to room temperature and stirred for an additional 5h. The reaction mixture was concentrated and the residue waschromatographed (Biotage 40M; 20% to 50% ethyl acetate-hexanes) toaffordN-benzyloxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-hydroxypropionamide(1.60 g).

Step 7

To a solution ofN-benzyloxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-hydroxypropionamide(3.0 g, 5.39 mmol) in argon deoxygenated 80% ethanol-tetrahydrofuran(160 mL) was added 10% Pd-C (1.3 g), and the resulting mixture washydrogenated at atmospheric pressure for 45 min. The reaction mixturewas degassed under argon and the slurry was filtered over Celite. TheCelite cake was washed with ample 80% ethanol-methylene chloride and thefiltrate was concentrated to almost dryness forcing the mixture tocrystallize. The slurry was filtered, washing with 50% diethylether-hexanes to affordN-hydroxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-hydroxypropionamide(2.38 g) as a white solid.

Example 6N-hydroxy-3-acetoxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]propionamide(Table I, Cmpd 14)

Step 1

To a solution ofN-benzyloxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-hydroxypropionamide(450 mg, 0.82 mmol) in pyridine (2 mL) at 0° C. was added aceticanhydride (0.09 mL, 0.98 mmol). The reaction mixture was allowed to warmto room temperature over 12 h and then partitioned between 2 N aqueoushydrochloric acid and methylene chloride (100 mL). The methylenechloride layer was separated, dried over magnesium sulfate, andconcentrated. Purification of the residue by preparative TLC (30% ethylacetate-hexanes) gaveN-benzyloxy-2(R)-[(3,4-methylenedioxy-benzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-acetoxypropionamide.

Step 2

To a solution ofN-benzyloxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-acetoxypropionamidedissolved in argon deoxygenated 80% ethanol-tetrahydrofuran (15 mL) wasadded 10% Pd-C (100 mg) and the resulting mixture was hydrogenated atatmospheric pressure for 45 min. The reaction mixture was degassed underargon and the slurry was filtered over Celite. The Celite cake waswashed with ample 80% ethanol-methylene chloride and the filtrate wasconcentrated. The crude mixture was dissolved in ethyl acetate (1-2 mL)and added slowly to rapidly stirring hexanes (100 mL) to produce aprecipitate. The precipitate was filtered and dried (50° C.; 1 torr) toaffordN-hydroxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-acetoxy-propionamide(171.3 mg) as a white powder.

Example 7N-Hydroxy-2(R)-[(4-methoxy-2,5,6-trimethylbenzenesulfonyl)-(1H-indol-5-ylmethyl)amino]-3-tert-butoxypropionamide(Table I, Cmpd 15)

Step 1

To a solution of 1H-indole-5-carboxylic acid (5 g, 31.0 mmol) in 70%methanol/methylene chloride (105 mL) at 0° C. was added 1Mtrimethylsilyldiazomethane in hexanes (46 mL, 46 mmol). After 45 min.,the reaction mixture was concentrated to afford 1H-indole-5-carboxylicacid methyl ester (5.2 g).

Step 2

To a solution of 1H-indole-5-carboxylic acid methyl ester (3.6 g, 20.6mmol) in tetrahydrofuran (180 mL) at 0° C., was added sodium hydride(0.65 g, 21.9 mmol). After 10 min., 2-trimethylsilanylethanesulfonylchloride (4.4 g, 21.9 mmol) was added and the reaction mixture wasallowed to warm to room temperature. After 3 h, acetic acid (1.6 mL,26.8 mmol) was added and the reaction mixture was concentrated. Thecrude product was chromatographed (Biotage 40M column, 2.5% ethylacetate-hexanes) to afford1-(2-trimethylsilanylethanesulfonyl)-indole-5-carboxylic acid methylester (5.43 g) as a white solid.

Step 3

To a solution of 1-(2-trimethylsilanylethanesulfonyl)indole-5-carboxylicacid methyl ester (7.4 g, 21.9 mmol) in tetrahydrofuran (100 mL) at −78°C. was added DIBALH® (44 mL, 1.5M, 65.5 mmol) in toluene. The reactionmixture was stirred for 45 min., at −78° C., 10 min. at 0° C., and 15min. at room temperature. The reaction mixture was recooled to −78° C.and ethyl acetate (100 mL) and saturated aqueous ammonium chloride (50mL) were added. The reaction mixture was allowed to warm to roomtemperature and a voluminous white precipitate was filtered over Celite.The biphasic mixture was extracted with ethyl acetate. The combinedorganic layers were washed with water, dried over magnesium sulfate, andconcentrated. The solid residue was triturated with 30% diethylether-hexanes and filtered to afford[1-(2-trimethyl-silanylethanesulfonyl)indol-5-yl]methanol (6.7 g) whichwas used in step 6 below.

Step 4

To a suspension of O-tert-butyl D-serine (2.66 g, 16.5 mmol) inacetonitrile (25 mL) was added trimethylsilyl cyanide (10 mL, 74.5 mmol)and the reaction mixture was heated to 80° C. for 1 h.4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride (4.3 g, 17.4 mmol) wasadded and the heating was continued. After 12 h, the reaction mixturewas cooled to room temperature and methanol (15 mL) was added. Thereaction mixture was concentrated in vacuo and the residue was dilutedwith diethyl ether (100 mL). The reaction mixture was cooled to 0° C.,and the pH adjusted to 8 using 6 N aqueous sodium hydroxide solution.The layers were partitioned and the aqueous layer was extracted withdiethyl ether. The aqueous layer was then adjusted to pH 4 and extractedwith ethyl acetate. The combined organic extracts were dried overmagnesium sulfate and concentrated to afford2(R)-2-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3-tert-butoxypropionicacid (5.1 g) as a brown foam which was used without furtherpurification.

Step 5

To a solution of2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3-tert-butoxypropionicacid (2.79 g, 7.5 mmol) in 70% methanol/methylene chloride (50 mL) at 0°C. was added 1M trimethylsilyldiazomethane in hexanes (22.5 mL, 23mmol). After 45 min., the reaction mixture was concentrated andchromatographed using preparative chromatography (9% ethylacetate-hexanes) to afford2(R)-(4-methoxy-2,3,6-trimethyl-benzenesulfonylamino)-3-tert-butoxypropionicacid methyl ester (2.4 g).

Step 6

To a solution of2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3-tert-butoxypropionicacid methyl ester (1.1 g, 2.84 mmol) in benzene (50 mL) at 0° C. wasadded [1-(2-trimethylsilylethanesulfonyl)indol-5-yl]methanol (1.33 g,4.26 mmol), tri-n-butylphosphine (1.07 mL, 4.26 mmol), followed by1,1′-[azodicarbonyl]dipiperidine (1.08 g, 4.26 mmol). The reactionmixture was allowed to warm to room temperature over 4 h. After 16 h,the reaction mixture was diluted with an equal volume of hexanes, cooledto 0° C. for 2 h and filtered. The residue was purified by preparativechromatography (20% ethyl acetate-hexanes) to afford2(R)-{(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-[1-(2-trimethylsilylethane-sulfonyl)indol-5-ylmethyl]amino-3-tert-butoxypropionicacid methyl ester (1.79 g) as a pale yellow oil.

Step 7

To a solution of2(R)-{(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-[1-(2-trimethylsilylethanesulfonyl)indol-5-ylmethyl]amino}-3-tert-butoxypropionicacid methyl ester (1.63 g, 2.55 mmol) in tetrahydrofuran (50 mL) wasadded 1M tetrabutylammonium fluoride (6.4 mL, 6.4 mmol) intetrahydrofuran, and the mixture heated to 40° C. After 1 h, thereaction mixture was partitioned between ethyl acetate and 1Mhydrochloric acid. The ethyl acetate layer was separated, dried overmagnesium sulfate, and concentrated. The residue was purified bypreparative chromatography (20% ethyl acetate-hexanes), to afford2(R)-{(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-[1H-indol-5-ylmethyl]amino}-3-tert-butoxypropionicacid methyl ester (1 g) which was taken directly into the next reaction.

Step 8

To a solution of2(R)-{(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-[1H-indol-5-ylmethyl]amino}-3-tert-butoxypropionicacid methyl ester (1.0 g, 1.94 mmol) in 50% methanol/tetrahydrofuran (10mL) was added a solution of LiOH.H₂O (160 mg, 3.88 mmol) in water (1mL). The reaction mixture was heated to 40° C. for 12 h and anadditional amount of LiOH.H₂O (160 mg, 3.88 mmol) in water (1 mL) wasadded. After 3 h, the aqueous solution was acidified to pH 3 using 2 Naqueous hydrochloric acid and the product was extracted into ethylacetate. The combined ethyl acetate layers were dried over magnesiumsulfate and concentrated to afford2(R)-[(1H-indol-5-ylmethyl)-(4-methoxy-2,3,6-trimethylbenzene-sulfonyl)amino]-3-tert-butoxypropionicacid (0.90 g).

Step 9

To a solution of2(R)-[(1H-indol-5-ylmethyl)-(4-methoxy-2,3,6-trimethylbenzene-sulfonyl)amino]-3-tert-butoxypropionicacid (0.90 g,1.8 mmol) was added O-benzyl hydroxylamine (0.67 g, 5.4mmol), 1-hydroxybenzotriazole (0.31 g, 1.98 mmol), N-methylmorpholine(0.36 g, 3.6 mmol), and 1-(dimethylaminopropyl)-3-ethylcarbodiimide(1.04 g, 5.4 mmol). After 16 h, the reaction mixture was diluted withethyl acetate (200 mL), washed with 2.4 N aqueous hydrochloric acid,saturated aqueous sodium bicarbonate, dried over magnesium sulfate, andconcentrated. Purification by preparative chromatography (3%methanol/methylene chloride) gave2(R)-N-benzyloxy-[(1H-indol-5-ylmethyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-tert-butoxypropionamide(0.85 g).

Step 10

To a solution of2(R)-N-benzyloxy-[(1H-indol-5-ylmethyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-tert-butoxypropionamide(0.80 g, 1.32 mmol) dissolved in argon deoxygenated 80%ethanol-tetrahydrofuran (100 mL) was added 10% Pd—C (0.4 g), and theresulting mixture was hydrogenated at atmospheric pressure for 60 min.The reaction mixture was degassed under argon, and the slurry wasfiltered over Celite. The Celite cake was washed with 80%ethanol-methylene chloride, and the filtrate was concentrated. The crudemixture was dissolved in ethyl acetate (5 mL) and slowly added to arapidly stirring hexanes (300 mL) to produce a precipitate which wasfiltered and dried (50° C.; 1 torr) to affordN-hydroxy-2(R)-[(1H-indol-5-ylmethyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-tert-butoxypropionamideas a white powder (500 mg).

Proceeding as described in Example 7 above, but substituting[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indol-5-yl]methanol with3,4-(methylenedioxy)phenyl methanol, gave2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)amino]-3-tert-butoxypropionamide.

Example 8N-hydroxy-2(R)-2-[(1H-indol-5-ylmethyl)-(4-methoxy-2,5-dimethylbenzenesulfonyl)-amino]-3-methylbutyramide(Table I, Cmpd 145)

Step 1

To a solution of 1H-indole-5-carboxylic acid methyl ester (16.8 g, 95.9mmol) in dry acetonitrile (150 mL) was added tert-butoxycarbonylanhydride (22 g, 100.8 mmol) followed by 4-dimethylaminopyridine (0.58g, 4.75 mmol). The reaction mixture was stirred for 3 h, thenconcentrated and chromatographed (300 g SiO₂, 5% ethyl acetate-hexanes)to afford N-tert-butoxycarbonylindole-5-carboxylic acid methyl ester(23.6 g) as a colorless oil.

Step 2

To a solution of N-tert-butoxycarbonylindole-5-carboxylic acid methylester (23.6 g, 85.7 mmol) in dry tetrahydrofuran (225 mL) at −78° C. wasadded 1.5 M DIBALH in toluene (171 mL, 257 mmol). After 2 h, thereaction mixture was quenched by the slow addition of methanol (45 mL),water (60 mL), and saturated aqueous NH₄Cl (30 mL). The cold bath wasremoved and after stirring for an additional 1 h, the reaction mixturewas filtered over Celite. The Celite cake was washed withtetrahydrofuran and the filtrate was concentrated to remove the morevolatile tetrahydrofuran. The biphasic mixture was extracted with ethylacetate. The combined organic layers were washed with water and theaqueous layer back extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over magnesium sulfate, andconcentrated to afford N-tert-butoxycarbonylindol-5-yl methanol (21.2g).

Step 3

To a solution of N-tert-butoxycarbonylindol-5-yl methanol (2.56 g, 10.35mmol) in dry methylene chloride (60 mL) was added manganese oxide (9 g,103.5 mmol). The reaction mixture was stirred for 3 h at roomtemperature and then heated at reflux. After 3 h, the heterogeneousslurry was filtered through Celite and concentrated to affordN-tert-butoxycarbonyl-5-formylindole (2.5 g).

Step 4

To a solution of D-valine benzyl ester hydrochloride (2.49 g, 10.21mmol) in dry methylene chloride (30 mL) was addedN-tert-butoxycarbonyl-5-formylindole (2.5 g, 10.21 mmol) and sodiumtriacetoxyborohydride (3.24 g, 15.29 mmol). The reaction mixture wasstirred for 15 h and then quenched with saturated aqueous sodiumbicarbonate. The aqueous layer separated and extracted with methylenechloride. The combined methylene chloride layers were washed with brine,dried over magnesium sulfate, and concentrated. The residue waschromatographed (Biotage 40M column, 10% ethyl acetate-hexanes) toafford 2(R)-[(N-tert-butoxycarbonylindol-5-yl)amino]-3-methylbutyramideO-benzyl ester (3.32 g) as a colorless oil.

Step 5

To a solution of2(R)-(N-tert-butoxycarbonylindol-5-yl)amino]-3-methylbutyramide O-benzylester (2.34 g, 5.36 mmol) in acetonitrile (15 mL) was addedtrimethylsilylcyanide (2.14 mL, 16.1 mmol). After 1 h,4-methoxy-2,5-dimethylbenzenesulfonyl chloride (3.18 g, 10.69 mmol) wasadded and the reaction mixture was heated to 70° C. for 16 h. Thereaction mixture was cooled to room temperature. Methanol (15 mL) wasthen added, and the reaction mixture was concentrated in vacuo. Theresidue was chromatographed (Biotage 40M column, 10% ethylacetate-hexanes) to afford2(R)-[(N-tert-butoxycarbonylindol-5-yl)-(4-methoxy-2,5-dimethylbenzenesulfonyl)amino]-3-methylbutyramideO-benzyl ester (1.56 g) as a colorless oil.

Step 6

To a solution of2(R)-[(N-tert-butoxycarbonylindol-5-yl)-(4-methoxy-2,5-dimethyl-benzenesulfonyl)amino]-3-methylbutyramideO-benzyl ester (0.45 g, 0.71 mmol) at 0° C. in methylene chloride (10mL) was added trifluoroacetic acid (2.5 mL). The reaction mixture wasstirred 40 min., then warmed to room temperature and stirred foradditional 2 h. The reaction mixture was diluted with ethyl acetate.This organic layer was separated and washed with saturated aqueoussodium bicarbonate, dried over magnesium sulfate, and concentrated. Theresidue was chromatographed (Biotage 40M column, 20% ethylacetate-hexanes) to afford2(R)-[(1H-indol-5-yl)-(4-methoxy-2,5-dimethyl-benzenesulfonyl)amino]-3-methylbutyramideO-benzyl ester (0.28 g) as a colorless oil.

Step 7

To solution of2(R)-[(1H-indol-5-yl)-(4-methoxy-2,5-dimethylbenzenesulfonyl)-amino]-3-methylbutyramideO-benzyl ester (1.1 g, 2.06 mmol) in argon deoxygenated 50%ethanol/tetrahydrofuran (30 mL) was added 10% Pd/C (0.6 g), and theresulting mixture was hydrogenated at atmospheric pressure. After 1.5 h,the reaction mixture was degassed under argon and the slurry wasfiltered over Celite. The Celite cake was washed with ample 80%ethanol/methylene chloride. The filtrate was concentrated and azeotropedwith tetrahydrofuran to give2(R)-[(1H-indol-5-yl)-(4-methoxy-2,5-dimethylbenzenesulfonyl)-amino]-3-methylbutyricacid (1.014 g), which was used in the next step without furtherpurification.

Step 8

To an ice cooled solution of2(R)-[(1H-indol-5-yl)-(4-methoxy-2,5-dimethyl-benzenesulfonyl)amino]-3-methylbutyricacid in dimethylformamide (20 mL) was added 1-hydroxybenzotriazolemonohydrate (384 mg, 2.51 mmol), O-benzylhydroxylamine (844 mg, 6.85mmol), N-methylmorpholine (462 mg, 4.57 mmol), and1-(dimethylaminopropyl)-3-ethylcarbodiimide (1.31 g, 6.85 mmol). Thereaction mixture was warmed to room temperature. After 16 h, thereaction mixture was partitioned between ethyl acetate (300 mL) and 1.5%aqueous hydrochloric acid (50 mL). The ethyl acetate layer was washedwith saturated aqueous sodium bicarbonate, dried over magnesium sulfateand concentrated. The residue was chromatographed (Biotage 40M column,50% EtOAc-Hexanes) to affordN-benzyloxy-2-[(1H-indol-5-ylmethyl)-(4-methoxy-2,5-dimethylbenzenesulfonyl)amino]-3-methyl-butyramidehydroxamate(0.61 g).

Step 9

To a solution ofN-benzyloxy-2-[(1H-indol-5-ylmethyl)-(4-methoxy-2,5-dimethylbenzenesulfonyl)amino]-3-methyl-butyramidehydroxamate(0.61 g, 1.1 mmol) in argon deoxygenated 50% ethanol/tetrahydrofuranmixture (20 mL) was added 10% Pd-C (600 mg). The resulting reactionmixture was hydrogenated at atmospheric pressure for 2 h. The reactionmixture was degassed under argon and the slurry was filtered overCelite. The Celite cake was washed with ample 80% ethanol/methylenechloride mixture and the filtrate was concentrated. The crude mixturewas dissolved in ethyl acetate (1 mL). This solution was slowly added arapidly stirring hexanes (100 mL) to produce a precipitate. Theprecipitate was filtered and dried (50° C.; 1 torr) to afford2(R)-N-Hydroxy-2-[(1H-indol-5-ylmethyl)-(4-methoxy-2,5-dimethylbenzenesulfonyl)amino]-3-methylbutyramide(477 mg) as a white powder.

Example 9N-hydroxy-2(R)-2-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzene-sulfonyl)amino]-3-methylbutyramide(Table I, Cmpd 40)

Step 1

To a solution of D-valine benzyl ester free base (12.92 g, 62 mmol) indry methylene chloride (120 mL) was added 3,4-(methylenedioxy)phenylmethanol (9.45 g, 62 mmol) and sodium triacetoxyborohydride (18.50 g,86.8 mmol). After 15 h, the reaction mixture was quenched with saturatedaqueous sodium bicarbonate (120 mL) and the aqueous layer was separatedand extracted with methylene chloride. The combined methylene chloridelayers were washed with brine, dried over magnesium sulfate, andconcentrated. The residue was chromatographed (300 g SiO₂, 5% ethylacetate-hexanes) to afford2(R)-(3,4-methylenedioxy-benzylamino)-3-methylbutyric acid benzyl ester(18 g) as a colorless oil.

Step 2

To a solution of 2(R)-(3,4-methylenedioxybenzylamino)-3-methylbutyricacid benzyl ester (3.0 g, 8.79 mmol) in acetonitrile (15 mL) was addedtrimethylsilyl cyanide (3.5 mL, 26.3 mmol). The reaction mixture washeated to 80° C. After 1 h, 4-methoxy-2,6-dimethylbenzenesulfonylchloride (3.14 g, 10.55 mmol) was added and heating was continued. After36 h, the reaction mixture was cooled to room temperature. Methanol wasadded (15 mL), and the solution was concentrated in vacuo. The residuewas chromatographed (Biotage 40M column, 10% ethyl acetate-hexanes) toafford2(R)-2-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-methylbutyricacid benzyl ester (4.33 g) as a colorless oil.

Step 3

To solution of2(R)-2-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethyl-benzenesulfonyl)amino]-3-methylbutyricacid benzyl ester (2.6 g, 4.81 mmol) in argon deoxygenated 50%ethanol/tetrahydrofuran mixture (20 mL) was added 10% Pd/C (2 g). Theresulting mixture was hydrogenated at atmospheric pressure for 3 h. Thereaction mixture was degassed under argon and the slurry filtered overCelite and washed with ample 80% ethanol/methylene chloride mixture. Thefiltrate was concentrated and azeotroped with tetrahydrofuran (22 mL)and the residue was dissolved in methylene chloride (20 mL). Thesolution was cooled to 0° C. and oxalyl chloride (0.8 mL, 9.17 mmol) and4 drops of dimethylformamide were added. The reaction mixture was warmedto room temperatuer, stirred 4 h and then concentrated. The crude acidchloride was then dissolved in methylene chloride (20 mL), cooled to 0°C., and N,O-bis-trimethylsilylhydroxylamine (4 mL, 18.7 mmol) was added.The reaction mixture was warmed to room temperatuer and after 3 hmethanol (20 mL) was added. After 30 min. the reaction mixture wasconcentrated and chromatographed using preparative TLC plates (5%methanol/methylene chloride) to affordN-hydroxy-2(R)-2-[(3,4-methylenedioxy-benzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-methylbutyramide(1.0 g).

Example 10N-Hydroxy-2(R)-[(4-methoxybenzenesulfonyl)-(1H-benzimidazol-5-ylmethyl)amino]-3-methylbutyramide(Table I, Cmpd 35)

Step 1

To an ice-cooled solution of2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid (7.0 g, 21.25mmol) in dry methylene chloride was addedN,N′-diisopropyl-O-tert-butylisourea (12.1 mL, 3.5M) via addition funnelover 45 min. The reaction mixture was maintained at 0° C. for 2 h andthen allowed to warm to room temperature overnight. The reaction mixturewas loaded onto a flash silica gel column and eluted with ethylacetate/hexane (5%) to give2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid tert-butylester (7.02 g) as a white crystalline solid.

Step 2

To a mixture of 4-amino-3-nitrobenzoic acid (10 g, 54.9 mmol) andtrimethylsilyl cyanide (20.6 mL, 3 equiv.) in dry acetonitrile (120 mL)was added o-phthaloyl-dichloride (7.9 mL, 54.9 mmol) and the materialwas heated to reflux. After 8 h, an additional amount of o-phthaloyldichloride (1 mL, 6.94 mmol) was added. After 16 h, the reaction mixturewas cooled to room temperature and ethyl acetate (100 mL) was added. Theorganic layer was separated and washed consecutively with equal volumesof 5% hydrochloric acid and then brine. The aqueous phases were backextracted with ethyl acetate (150 mL). The residue was crystallized fromhot ethyl acetate/hexane to give 3-nitro-4-(aminophthaloyl)benzoic acid(5.85 g) as a crystalline brown solid.

Step 3

To a mixture of 3-nitro-4-(aminophthaloyl)benzoic acid (5.85 g, 18.74mmol) and diisopropylethylamine (3.9 mL, 22.49 mmol) in tetrahydrofuran(120 mL) was added benzotriazol-1-yloxy-tris-(dimethylamino)phosphoniumhexafluorophosphate (9.95 g, 22.49 mmol). The material was stirred for 5min. Sodium borohydride (744 mg, 19.7 mmol) was added in three portionsover 5 min. and the reaction mixture was stirred for 0.5 h. Ethylacetate (100 mL) was added and the organic phase was washedconsecutively with equal volumes of 5% hydrochloric acid, 5% sodiumbicarbonate, and brine and back extracted with ethyl acetate (150 mL).The organic phase was condensed on the rotoevaporator and the residuewas purified by flash silica gel chromatography using ethylacetate/hexane (50%) as eluant, to provide3-nitro-4-(aminophthaloyl)benzyl alcohol as a yellow solid (4.61 g).

Step 4

To a mixture of 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyricacid tert-butyl ester (1.91 g, 5.6 mmol),3-nitro-4-(aminophthaloyl)benzyl alcohol (1.75 g, 5.87 mmol) andtributylphophine (1.5 mL, 5.87 mmol) in dry benzene (40 mL) was added(1,1′-azo-dicarbonyl)dipiperidine (1.48 g, 5.87 mmol). The reactionmixture was stirred overnight and then loaded onto a flash silica gelcolumn. The column was eluted with ethyl acetate/hexane (5-15%) to give2(R)-{[(3-nitro-4-(aminophthaloyl)benzyl]-(4-methoxybenzenesulfonyl)-amino}-3-methylbutyricacid tert-butyl ester (437 mg).

Step 5

To a solution of2(R)-{[(3-nitro-(4-aminophthaloyl)benzyl]-(4-methoxybenzene-sulfonyl)amino}-3-methylbutyricacid tert-butyl ester (420 mg, 0.673 mmol) in ethanol/tetrahydrofuran(15 mL of 1:1 ratio) was added 10% Pd/C (40 mg). The reaction mixturewas placed under a hydrogen balloon and stirred for 4 h. The reactionmixture was filtered through a short plug of Celite (2 g, on a sinteredglass funnel) and washed well with ethanol (100 mL). The filtrate wasconcentrated to give2(R)-{[(3-amino-(4-aminophthaloyl)benzyl]-(4-methoxybenzenesulfonyl)amino}-3-methylbutyricacid tert-butyl ester (375 mg).

Step 6

To a solution of2(R)-{[(3-amino-4-(aminophthaloyl)benzyl]-(4-methoxybenzene-sulfonyl)amino}-3-methylbutyricacid tert-butyl ester (370 mg, 0.623 mmol) in methanol/methylenechloride (12 mL, ratio of 1:1) is added hydrazine (0.39 mL, 20 equiv.).The reaction mixture was stirred for 16 h. The reaction mixture wasfiltered and the filtrate concentrated on a rotoevaporator. A residuewas filtered and the filtrate was again concentrated on theroto-evaporator to provide2(R)-{[(3,4-diamino)benzyl]-(4-methoxy-benzenesulfonyl)amino}-3-methylbutyricacid tert-butyl ester (288 mg).

Step 7

To a mixture of2(R)-{[(3,4-diamino)benzyl]-(4-methoxybenzenesulfonyl)amino}-3-methylbutyricacid tert-butyl ester (90 mg, 0.194 mmol) and trimethyl orthoformate(0.022 mL, 1.05 equiv.) in dry toluene (10 mL) was added KSFmontmorillonite clay (25 mg). The reaction mixture was heated at refluxfor 6.5 h and then cooled to room temperature. After reaching roomtemperature, the mixture was condensed in vacuo and the residue wasloaded onto a preparatory thin layer chromatography plate. Elution withmethanol/methylene chloride (10%) provided2(R)-[(benzimidazol-5-ylmethyl)-(4-methoxy-benzenesulfonyl)amino]-3-methylbutyricacid tert-butyl ester (79 mg).

Step 8

A solution of2(R)-[(benzimidazol-5-ylmethyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyricacid tert-butyl ester (74 mg, 0.156 mmol) in a 1:4 trifluoroaceticacid/methylene chloride mixture (5 mL) was stirred for 2 h. The reactionmixture was concentrated on a roto-evaporator and then on high-vac pumpto give2(R)-[(benzimidazol-5-ylmethyl)-(4-methoxy-benzenesulfonyl)amino]-3-methylbutyricacid (approx. 0.135 mmol).

Step 9

To a solution of2(R)-[(benzimidazol-5-ylmethyl)-(4-methoxybenzenesulfonyl)-amino]-3-methylbutyricacid (0.13 mmol), O-benzylhydroxylamine (0.1 mL, 0.52 mmol),1-hydroxybenzo-triazole hydrate (24 mg, 0.16 mmol), andN-methylmorpholine (0.05 mL, 0.39 mmol) in anhydrous dimethylformamide(10 mL) was added 1-ethyl-3(3-dimethylamino)-propyl carbodiimidehydrochloride salt (45 mg, 0.24 mmol). The reaction mixture was stirredovernight and then condensed on the roto-evaporator. The residue wastaken up in ethyl acetate (40 mL) and washed consecutively with equalvolumes of 2% aqueous ammonium chloride, 5% sodium bicarbonate, andbrine and then concentrated in vacuo. The residue was purified bypreparative thin layer chromatography using methanol/methylene chloride(10%) as eluant to give2(R)-N-benzyloxy-[(benzimidazol-5-ylmethyl)-(4-methoxybenzene-sulfonyl)amino]-3-methylbutyramide(48 mg, 71%).

Step 10

To a solution of2(R)-N-benzyloxy-[(benzimidazol-5-ylmethyl)-(4-methoxybenzene-sulfonyl)amino]-3-methylbutyramide(42 mg, 0.08 mmol), in a 3:1 mixture of ethanol/tetrahydrofuran (10 mL),was added 10% Pd/C (40 mg). The reaction mixture was placed under ahydrogen balloon. After 2 h, the reaction mixture was filtered through ashort plug of Celite (1 g on a sintered glass funnel) and the Celite padwas washed with ethanol (100 mL). The filtrate was concentrated on aroto-evaporator and the residue was purified by preparative thin layerchromatography using methanol/methylene chloride (10%) as the eluent togiveN-hydroxy-2(R)-[(benzimidazol-5-ylmethyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyramide(23 mg).

Example 11N-hydroxy-2(R)-[(1H-3-acetyl-indol-5-ylmethyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyramide(Table I, Cpd. 126)

Step 1

To an oven dried flask, under nitrogen atmosphere containing2(R)-[(1H-indol-5-ylmethyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyricacid methyl ester, (1.41 g, 2.98 mmol), [prepared by the method ofExample 2, Step 1, and instead of Example 2, Step 2 (alkylation of thecarboxylic acid with benzyl bromide), the methyl ester is formed usingtrimethylsilydiazomethane (see Example 3, Step 1)], was addedN,N-dimethylacetamide (1.75 ml, 14.9 mmol) followed by dropwise additionof phosphorus oxychloride (1.4 ml, 11.92 mmol), with vigorous stirring.After complete addition the mixture was heated (80-90° C., oil bath) for3.5 hours. The material was cooled to ambient temperature and 1 N sodiumhydroxide was added with vigorous mechanical stirring. After fiveminutes methylene chloride and water (1:1; 120 ml) were added and thematerial was partitioned and the organic phase collected. The methylenechloride phase was then washed consecutively with equal volumes of waterand brine and the aqueous phases were back extracted with methylenechloride (2×60 ml). The combined organic phases were dried withmagnesium sulfate, filtered and condensed. The residue was purified bypreparative thin layer chromatography on silica gel using 3%methanol-methylene chloride as eluant, providing2(R)-[(1H-3-acetyl-indol-5-ylmethyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyricacid methyl ester (815 mg) as a golden viscous oil.

Step 2

To a solution of2(R)-[(1H-3-acetyl-indol-5-ylmethyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyricacid methyl ester (805 mg, 1.56 mmol), in methanol (30 ml) was added aaqueous solution of 1.0 N lithium hydroxide (3.1 ml). The mixture washeated under reflux for 12 hours. Extra 1.0 N lithium hydroxide (3.1 ml)was added and the mixture heated for an additional eight hours. Thematerial was cooled to ambient temperature and concentrated in vacuo andthe residue taken up in water-ether (1:1, 50 ml). The layers werepartitioned and the aqueous layer was collected and acidified (5%aqueous HCl to pH=3) in the presence of an equal volume of ethylacetate. The ethyl acetate phase was collected and washed with an equalvolume of brine. The aqueous phases were back extracted with ethylacetate (2×80 ml), combined, dried with magnesium sulfate, filtered andcondensed to provide2(R)-[(1H-indol-3-acetyl-5-ylmethyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyricacid, (586 mg) as a tan colored solid powder.

Step 3

To a mixture of2(R)-[(1H-3-acetyl-indol-5-ylmethyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyricacid (580 mg, 1.16 mmol), 2,4-dimethoxybenzyl hydroxylamine (255 mg,5.15 mmol), 1-hydroxybenzotriazole hydrate (178 mg, 1.16 mmol), andN-methyl morpholine (0.2 ml, 1.74 mmol) in dry dimethyl formamide wasadded 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride salt(333 mg, 1.74 mmol). The reaction mixture was stirred overnight and thenconcentrated on the rotary evaporator-pump. The residue was taken up inethyl acetate (80 ml) and a 2% aqueous solution of ammonium chloride (80ml) and partitioned. The organic phase was collected and washedconsecutively with equal volumes of 5% aqueous sodium bicarbonate andbrine. The aqueous phases were back extracted with ethyl acetate (2×80ml) and the combined organic phases were dried over magnesium sulfateand concentrated in vacuo to afford crudeN-(2,4-dimethoxy)benzyloxy-2(R)-[(1H-3-N-(2,4-dimethoxybenzyloxyiminoacetyl)-indol-5-ylmethyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyramide, which was taken directly into the next stepwithout further purification.

Step 4

To a solution ofN-(2,4-dimethoxy)benzyloxy-2(R)-[(1H-3-N-(2,4-dimethoxybenzyloxyiminoacetyl)-indol-5-ylmethyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyramide (assumed 1.1 mmol) in 5% trifluoroaceticacid-tetrahydrofuran (15 ml) and water (2 ml) was added triethylsilane(0.7 ml, 3.9 mmol). The mixture was stirred for one hour at ambienttemperature and then extra trifluoroacetic acid (0.5 ml) was added. Thematerial was heated (60-70° C.) under nitrogen atmosphere. After 0.5hour additional trifluoroactic acid (0.5 ml) was added and heating wasmaintained for a total of four hours. The mixture was cooled to ambienttemperature and diluted with water (60 ml) and ethyl acetate (60 ml).The material was partitioned and the organic phase collected and washedwith an equal volume of brine. The aqueous phases were back extractedwith ethyl acetate (2×60 ml), combined and dried with magnesium sulfate.The material was condensed and the residue purified by preparative thinlayer chromatography on silica gel, using 10% methanol-methylenechloride as eluant, providingN-hydroxy-2(R)-[(1H-3-acetyl-indol-5-ylmethyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyramide(320 mg) as a tan solid powder.

Example 12N-hydroxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-(methanesulfonyl)amino-propionamide(Table 1, Cpd. 128)

Step 1

To an ice-cooled solution of N-BOC-D-serine (10 g, 48.7 mmol) inmethylene chloride (50 ml) was addedN,N′-diisopropyl-O-tert-butylisourea (35 ml, 3.5 M) via addition funnel,over 30 min. The reaction mixture was maintained at 0° C. for 2 hrs andthen warmed to room temperature over night. The material was againcooled to 0° C. and a second portion ofN,N′-diisopropyl-O-tert-butylisourea (28 ml, 3.5 M) was added. Thematerial was stirred for 2 hrs at 0° C. and then warmed again to roomtemperature over night. Purification by flash silica gel chromatographyusing (20%) ethyl acetate/hexanes as eluant gaveO-tert-butyl-N-BOC-D-serine (7.97 g) as a viscous oil which solidifiedon standing.

Step 2

To a solution of O-tert-butyl-N-BOC-D-serine (4 g, 15.31 mmol),phthalimide (3.38 g, 22.9 mmol) and triphenyl phosphine (6.03 g, 22,9mmol) in tetrahydrofuran (120 ml, anhydrous) was added diisopropylazodicarboxylate (4.5 ml, 22.9 mmol). The mixture was stirred undernitrogen atmosphere over night. The tetrahydrofuran was removed on theroto-evaporator and the remainder was taken up in methylene chloride (60ml) and loaded onto a flash silica gel column. Elution with ethylacetate/hexanes (19%) gavetert-butyl-2(R)-[(tert-butoxycarbonyl)amino]-3-phthalimido-propionate(3.74 g) as a white powder.

Step 3

Tert-butyl-2(R)-[(tert-butoxycarbonyl)amino]-3-phthalimido-propionate(8.58 g, 21.8 mmol) was taken up in a anhydrous solution of hydrochloricacid in dioxane (100 ml, 4% wt/wt). The reaction flask was fitted with arotovap trap, which was topped with a teflon stopper and the mixture washeated to 80° C. (use a plexiglass shield for safety). After 1.5 hoursthe material was cooled to ambient temperature and all volatiles removedon the rotary evaporator. The white solid was taken up in methylenechloride (100 ml) and transferred to a seperatory funnel. The solutionwas partitioned with an equal volume of aqueous sodium hydroxide (1.0 N)and the organic phase collected. This was subsequently shaken with brinesolution (2×100 ml, consecutively) and the aqueous phases back extractedwith methylene chloride (3×100 ml). The organic phases were combined,dried (MgSO₄), filtered and condensed to providetert-butyl-2(R)-amino-3-phthalimido-propionate (5.7 g) as a whitepowder.

Step 4

To a stirred solution of tert-butyl-2(R)-amino-3-phthalimido-propionate(5.7 g, 19.63 mmol) in dry acetonitrile (60 ml) was addedtrimethylsilylcyanide (8.6 ml, 68.7 mmol). After 5 minutes2,6-dimethyl-4-methoxybenzenesulfonyl chloride (4.84 g, 20.6 mmol) wasadded in one portion. The material was stirred at ambient temperaturefor 1 hour and then ethyl acetate (80 ml) was added and the mixture wastransferred to a seperatory funnel. The organic phase was partioned withaqueous hydrochloric acid (1.5%, 100 ml), collected and washed with anequal volume of brine. The aqueous phases were back extracted with ethylacetate (2×80 ml) and the organic phases combined, dried (magnesiumsulfate), filtered and condensed. The residue was chromatographed (flashsilica gel, 30% ethyl acetate-hexanes) to provide tert-butyl2(R)-(2,6-dimethyl-4-methoxybenzenesulfonylamino)-3-phthalimido-propionate as white semi-solid (6.9 g).

Step 5

To a cooled (ice bath) solution of tert-butyl2(R)-(2,6-dimethyl-4-methoxybenzenesulfonylamino)-3-phthalimido-propionate (6.9 g, 14.12 mmol) in drybenzene (150 ml) with piperonyl alcohol (3.22 g, 21.2 mmol) and tributylphosphine (5.3 ml, 21.2 mmol) was added1,1′-(azodicarbonyl)-dipiperidine (5.35 g,, 21.2 mmol). The mixture wasallowed to warm to ambient temperature overnight. The material wasloaded onto a flash silica gel column using ethyl acetate-hexanes (30%)as eluant, providing tert-butyl2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-phthalimido-propionateas a white solid (8.59 g).

Step 6

To a stirred solution of tert-butyl2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-phthalimido-propionate(3.9 g, 6.2 mmol) in a mixture of 78% methylene chloride/methanol (47ml) was added hydrazine hydrate (3.9 ml, 125 mmol) and the mixture wasstirred for five hours, at which time a solid precipitate ofphthalhydrazide was observed to form. The material was filtered, washingwith methylene chloride, to remove the precipitate. The filtrate wasthen evaporated on the rotovap and taken up in methylene chloride (80ml) and transferred to a separatory funnel. After partitioning with anequal volume of water, the organic phase was collected and washed withan equal volume of brine. The aqueous phases were back extracted withmethylene chloride (2×80 ml). The methylene chloride phases werecombined, dried (MgSO₄), filtered and condensed to provide tert-butyl2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-amino-propionateas a white semi-solid (3.0 g).

Step 7

To a mixture of tert-butyl2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-amino-propionate(1.02 g, 2.0 mmol), with trimethylsilyl cyanide (0.7 ml, 5.2 mmol) indry acetonitrile (15 ml) was added methanesulfonyl chloride (0.18 ml,2.3 mmol) and the material was stirred overnight. Ethyl acetate (80 ml)was added and the material was partitioned with aqueous hydrochloricacid (1.5%, 80 ml). The organic phase was collected and washed with anequal volume of brine; The aqueous phases were back extracted with ethylacetate (2×80 ml) and the organic phases combined, dried (MgSO₄),filtered and condensed to provide tert-butyl2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionateas a pale yellow semi-viscous oil (1.4 g).

Step 8

A solution of tert-butyl2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionate(1.37 g, 2 mmol) in 20% trifluoracetic acid-methylene chloride (15 ml)was stirred for 1 hour. Extra trifluoroacetic acid (0.5 ml) was addedand stirring continued for two hours. The material was then condensed onthe rotary evaporator and the residue was taken up in toluene (40 ml)and again condensed. This procedure was repeated twice (2×40 ml toluene,to remove traces of trifluoracetic acid) to provide2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionicacid as a tan green foamy solid (1.02 g).

Step 9

To a mixture of2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionicacid (1 g, 1.9 mmol), O-benzylhydroxylamine (0.95 ml, 6 mmol) and1-hydroxybenzotriazole hydrate (370 mg, 1.9 mmol), andN-methylmorpholine (0.7 ml, 5.7 mmol) in anhydrous dimethylformamide (20ml) was added 1-ethyl-3(3-dimethylamino)-propyl carbodiimidehydrochloride salt. The mixture was stirred overnight and then condensedon the roto-evaporator. The remainder was taken up in ethyl acetate (60ml) and partitioned with an equal volume of 5% aqueous hydrochloricacid. The ethyl acetate phase was collected and washed consecutivelywith equal volumes of 5% sodium bicarbonate and brine. The aqueousphases were back extracted with ethyl acetate (2×60 ml) and the organiclayers combined, dried with magnesium sulfate, filtered and condensed.The residue was purified by preparative thin layer chromatography using65% ethyl acetate-hexanes as eluant providing N-benzyloxy2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionamideas a yellow viscous oil (591 mg).

Step 10

To a solution ofN-benzyloxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionamide(580 mg, 0.94 mmol) in a 3:1 mixture of ethanol/tetrahydrofuran (30 ml)was added 10% palladium on charcoal (60 mg). The reaction mixture wasplaced under a hydrogen balloon and stirred for 6 hours. The materialwas filtered through a short plug of silica, rinsing with ethanol (200ml). The filtrate was condensed on the roto-evaporator and the residuewas purified by preparative thin layer chromatography using 8.5%methanol-methylene chloride as eluant providingN-hydroxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionamideas a tan powder (223 mg).

Replacement of methanesulfonyl chloride in Step 7 with:

benzenesulfonyl chloride,

acetyl chloride,

benzoyl chloride,

4-methoxycarbonyl-benzoyl chloride, and

methyl chloroformate; gave

N-hydroxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-benzenesulfonylamino-propionamide,(Table 1, Cpd. 129)

N-hydroxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-acetylamino-propionamide,(Table 1, Cpd. 130)

N-hydroxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-benzoylamino-propionamide,Table I, Cpd. 138)

N-hydroxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-(4-methoxycarbonyl-benzoyl)amino-propionamide,(Table I, Cpd. 133) and

N-hydroxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methoxycarbonylamino-propionamide(Table I, Cpd. 131).

Example 13N-hydroxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-[(2-pyrrol-1-yl)-phenylcarbonylamino]-propionamide(Table I, Cmpd. 143)

Step 1

To a mixture oftert-butyl-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-amino-propionate(1.02 g, 2.0 mmol), 1-(2-carboxyphenyl)pyrrole (581 mg, 3.1 mmol),1-hydroxybenzotriazole hydrate (279 mg, 2.0 mmol), N-methylmorpholine(0.8 ml, 7.3 mmol) and 4-dimethylaminopyridine (30 mg, 0.25 mmol) in drydimethylformamide (25 ml) was added 1-ethyl-3,3-dimethylamino)-propylcarbodiimide hydrochloride salt (600 mg,, 3.1 mmol) and the material wasstirred overnight. The dimethylformamide was removed on the rotaryevaporator and the residue was taken up in ethyl acetate (80 ml) andpartitioned with an equal volume of aqueous hydrochloric acid (1.5%, 80ml). The organic phase was collected and washed with equal volumes of 5%aqueous sodium bicarbonate and then brine. The aqueous phases were backextracted with ethyl acetate (2×80 ml) and the organic phases combined,dried over magnesium sulfate, filtered and condensed to provide aresidue. This material was chromatographed using preparative TLC plates(45% ethyl acetate/hexanes) to affordtert-butyl-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-[(2-pyrrol-1-yl)phenylcarbonylamino]-propionate)as a pale yellow foamy solid (927 mg).

Step 2

A solution oftert-butyl-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-[(2-pyrrol-1-yl)phenylcarbonylamino]-propionate(915 mg, 1.3 mmol) in 20% trifluoracetic acid-methylene chloride (15 ml)was stirred for 1 hour. Extra trifluoroacetic acid (0.5 ml) was addedand stirring continued for 1.5 hours. The material was then condensed onthe rotary evaporator and the residue was taken up in toluene (40 ml)and again condensed. This procedure was repeated twice (2×40 ml toluene,to remove traces of trifluoracetic acid) to provide2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-[(2-pyrrol-1-yl)phenylcarbonylamino]-propionicacid as a golden tan solid (896 mg).

Step 3

To a mixture of2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-[(2-pyrrol-1-yl)phenylcarbonylamino]-propionicacid (approximately 1.3 mmol), O-benzylhydroxylamine (0.6 ml, 3.9 mmol)and 1-hydroxybenzotriazole hydrate (199 mg, 1.3 mmol), andN-methylmorpholine (0.44 ml, 3.9 mmol) in anhydrous dimethylformamide(20 ml) was added 1-ethyl-3(3-dimethylamino)-propyl carbodiimidehydrochloride salt (375 mg, 1.95 mmol). The mixture was stirredovernight and then condensed on the roto-evaporator. The remainder wastaken up in ethyl acetate (60 ml) and partitioned with an equal volumeof 1.5% aqueous hydrochloric acid. The ethyl acetate phase was collectedand washed consecutively with equal volumes of 5% sodium bicarbonate andthen brine. The aqueous phases were back extracted with ethyl acetate(2×60 ml) and the organic layers combined, dried with magnesium sulfate,filtered and condensed. The residue was purified by preparative TLC (2%methanol-methylene chloride) providingN-benzyloxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-[(2-pyrrol-1-yl)phenylcarbonylamino]-propionamideas a light yellow foamy solid (490 mg).

Step 4

To a solution ofbenzyloxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-(2′pyrrolo)benzamido-propionamide(480 mg, 0.675 mmol) in a 3:1 mixture of ethanol/tetrahydrofuran (30 ml)was added 10% palladium on charcoal (60 mg). The reaction mixture wasplaced under a hydrogen balloon and stirred for 8 hours during whichtime additional catalyst (2×60 mg) was added. The material was filteredthrough a short plug of silica, rinsing with ethanol (200 ml). Thefiltrate was condensed on the roto-evaporator and the residue waspurified by preparative TLC (7% methanol-methylene chloride) providing amixture ofN-hydroxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-[(2-pyrrol-1-yl)phenylcarbonylamino]-propionamideandN-hydroxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-[(2-pyrrolidin-1-yl)phenylcarbonylamino]-propionamide(82:18) as a tan powder (216 mg).

Example 14N-hydroxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3(S)-hydroxybutyramide(Table I, Cmpd. 94)

Step 1

To a suspension of D-threonine (7.87 g, 66.1 mmol) in acetonitrile (100mL) was added trimethylsilyl cyanide (40 mL, 298 mmol) and the resultingsolution was heated to 80° C. After 1 h,4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride (17.3 g, 69.4 mmol)was added and the heating was continued. After 12 h, the reactionmixture was cooled to room temperature. Methanol (15 mL) was added, andthe organics were removed in vacuo. The residue was diluted with diethylether (300 mL) and after cooling the reaction mixture to 0° C., the pHwas adjusted to 8 with 6 N aqueous sodium hydroxide solution. Theorganic layer was collected and the aqueous layer was extracted withdiethyl ether. The aqueous layer was adjusted to pH 4 and againextracted with ethyl acetate. The combined organic extracts were driedover magnesium sulfate and concentrated to afford2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3(S)-hydroxybutyricacid (22 g) as a brown foam which was used without further purification.

Step 2

To a solution of2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3(S)-hydroxybutyricacid (29.13 g, 87.9 mmol) in dimethylformamide (280 mL) at 0° C., wasadded potassium carbonate (72.9 g, 527 mmol) and a solution of3,4-methylenedioxybenzyl chloride ((60 g, 170.8 mmol, 50% (w/w)) inmethylene chloride. After 2 h, lithium iodide (5.88 g, 44 mmol) wasadded and the reaction mixture was warmed to rt. over 2 h. After 6 h,the reaction mixture was partitioned between ethyl acetate (600 mL) andwater (250 mL). The organic layer was separated, dried over magnesiumsulfate and concentrated in vacuo. The crude residue was chromatographed(300 g SiO₂, 15% ethyl acetate-hexanes) to afford2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3(S)-hydroxy-butyricacid 3,4-methylenedioxybenzyl ester (40.4 g), a portion which was takendirectly into the next reaction without further purification.

Step 3

2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3(S)-hydroxybutyricacid 3,4-methylenedioxybenzyl ester (10.9 g, 23.41 mmol) and imidazole(2.07 g, 30.43 mmol was dissolved in tetrahydrofuran (28 mL). Thereaction mixture was cooled to 0° C. and 1 M triethylsilyl chloride intetrahydrofuran (28 mL, 28 mmol) was added. After 1 h, the reactionmixture was concentrated and chromatographed over a Biotage 40L column(eluted with 10% ethyl acetate-hexanes) to afford2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl-amino)-3(S)-(triethylsilyloxy)butyricacid 3,4-methylenedioxybenzyl ester (13.5 g).

Step 4

To a solution of2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl-amino)-3(S)-(triethylsilyloxy)butyricacid 3,4-methylenedioxybenzyl ester (3.3 g, 5.7 mmol) in benzene (100mL) at 0° C. was added 3,4-methylenedioxyphenyl methanol (1.3 g, 8.5mmol), tri-n-butylphosphine (2.1 mL, 8.5 mmol), followed by1,1′-[azodicarbonyl]dipiperidine (2.2 g, 8.5 mmol). The reaction mixturewas allowed to warm to room temperature over 4 h. After 72 h, thereaction mixture was diluted with an equal volume of hexanes, cooled to0° C. for 2 h and filtered. The residue was concentrated andchromatographed (300 g SiO₂, 15% ethyl acetate-hexanes) to afford2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3(S)-(triethylsilyloxy)butyricacid 3,4-methylenedioxybenzyl ester (3.3 g) as a yellow oil.

Step 5

To a solution of2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzene-sulfonyl)amino]-3(S)-(triethylsilyloxy)butyricacid 3,4-methylenedioxybenzyl ester (3.3 g, 4.62 mmol) in argondeoxygenated 80% ethanol-tetrahydrofuran (100 mL) was added 10% Pd-C (2g) and the resulting reaction mixture was hydrogenated at atmosphericpressure for 45 min. The reaction mixture was degassed under argon, theslurry was filtered over Celite, and the Celite pad was washed withample 80% ethanol-methylene chloride. The filtrate was concentrated andazeotroped with tetrahydrofuran (200 mL) and the residue was dissolvedin dimethylformamide (25 mL). O-Benzyl hydroxylamine (2.0 g,16.2 mmol),HOBT (0.71 g, 5.2 mmol), and EDAC (3.1 g, 16.2 mmol) were added and thereaction mixture was stirred for 16 h. The reaction mixture was dilutedwith ethyl acetate and was washed with 2.4 N aqueous hydrochloric acidand saturated aqueous sodium bicarbonate. The mixture was then driedover magnesium sulfate and concentrated in vacuo to afford crudeN-benzyloxy-2(R)-[(3,4-methylenedioxy-benzyl)-(4-methoxy-2,3,6-trimethylbenzene-sulfonyl)amino]-3(S)-hydroxybutyramide(1.25 g) which was taken directly into the next reaction without furtherpurification.

Step 6

To a solution ofN-benzyloxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3(S)-hydroxybutyramide(1.25 g, 2.19 mmol) in argon deoxygenated 80% ethanol-tetrahydrofuran(100 mL) was added 10% Pd-C (0.7 g), and the resulting mixture washydrogenated at atmospheric pressure for 60 min. The reaction mixturewas degassed under argon and the slurry was filtered over Celite. TheCelite cake was washed with ample 80% ethanol-methylene chloride and thefiltrate was concentrated to almost dryness. The mixture was dissolvedin 4 mL of ethyl acetate which was added slowly dropwise to 100 mL ofvigorously stirring hexanes. The slurry was filtered to affordN-hydroxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3(S)-hydroxybutyramide(0.67 g) as a white solid.

Example 15N-hydroxy-2(R)-[(1H-benzimidazole-5-ylmethyl)(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3(R)-hydroxybutyramide(Table I, Cmpd. 136)

Step 1

The conditions for the esterification of N-carbobenzyloxy-D-threoninewith N,N′-diisopropyl-O-tert-butylisourea to provideO-tert-butyl-N-carbobenzyloxy-D-threonine are the same as thosedescribed in Example 12, step 1 above.

Step 2

To a mixture of O-tert-butyl-N-carbobenzyloxy-D-threonine (2.74 g, 8.86mmol), triethylamine (1.9 ml, 13.29 mmol) and 4-dimethylaminopyridine(50 mg) in dry dimethylformamide (20 ml) was addedtert-butyldimethylsilyl chloride (1.47 g, 9.8 mmol). The mixture wasstirred overnight under argon atmosphere. Additional triethylamine (1ml) and tert-butyldimethsilyl chloride (500 mg) were added, and themixture was heated at 80° C. for six hours. The material was cooled toambient temperature and condensed on the rotary evaporator. The residuewas taken up in methylene chloride (80 ml) and partitioned with an equalvolume of brine. The organic phase was collected and the aqueous phasewas back extracted with methylene chloride (2×80 ml). The methylenechloride phases were combined, dried with magnesium sulfate andcondensed. The residue was purified by chromatography (flash silica gel,15% ethyl acetate-hexanes) to provideO-tert-butyl-N-carbobenzyloxy-β-O-tert-butyldimethylsilyl-D-threonine(3.27 g) as a clear viscous oil.

Step 3

To a solution ofO-tert-butyl-N-carbobenzyloxy-β-O-tertbutyldimethylsilyl-D-threonine(3.26 g, 7.7 mmol) in a 3:1 mixture of ethanol/tetrahydrofuran (30 ml)was added 10% palladium on charcoal (80 mg). The mixture was placedunder a hydrogen balloon and stirred for 1.5 hours. The material wasfiltered through a short plug of celite and rinsed with ethanol (200ml). The filtrate was condensed on the rotary evaporator providingα-O-tert-butyl-β-O-tertbutyldimethylsilyl-D-threonine (2.2 g) as a clearviscous oil.

Step 4

To a stirred solution(α-O-tert-butyl-(β-O-tertbutyldimethylsilyl-D-threonine (2.15 g, 7.65mmol) in dry acetonitrile (30 ml) was added trimethylsilylcyanide (2.9ml, 22.9 mmol). After five minutes2,3,6-trimethyl-4-methoxybenzenesulfonyl chloride (2.02 g, 8.1 mmol) wasadded and the mixture was stirred for two hours. Ethyl acetate (80 ml)was added and the material was partitioned with an equal volume ofaqueous 1.5% hydrochloric acid. The organic phase was collected andshaken with an equal volume of brine. The ethyl acetate phase wasisolated and the aqueous phases were back extracted with ethyl acetate(2×80 ml). The organic phases were combined, dried with magnesiumsulafate and condensed to providetert-butyl-2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-[(R)-tert-butyldimethylsilyloxy]-butyrate(3.85 g) as a foamy semi-solid material.

Step 5

To a solution oftert-butyl-2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-[(R)-tert-butyldimethylsilyloxy]-butyrate(3.83 g, 7.63 mmol) and 3-nitro-4-(N-phthaloyl)benzyl bromide (3.03 g,8.4 mmol) in dry dimethylformamide (30 ml) was added potassium carbonate(1.7 g, 12.3 mmol) (Note: the synthesis for 3-nitro-4(N-phthaloyl)benzylbromide is shown below in Step 5A). The mixture was stirred for 12 hoursand additional 3-nitro-4-(N-phthaloyl)benzyl bromide (1.0 g) was added.After another 6 hours the mixture was condensed on the rotaryevaporator. Purification by chromatography (silica gel, 10% to 15% ethylacetate-hexanes) providedtert-butyl-2(R)-[(3-nitro-4-(N-phthalamido)benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino)]-3-[(R)-tert-butyldimethylsilyloxy]-butyrateas a white powder (4.36 g).

Step 5A

Preparation of 3-nitro-4-(aminophthaloyl)benzyl bromide:

To a cooled (ice bath) solution of 3-nitro-4-(aminophthaloyl)benzylalcohol (5.94 g, 19.92 mmol) [the synthesis of this alcohol wasdescribed in example 10, steps 2 & 3] and triphenylphosphine (7.83 g,29.9 mmol) in dry methlylene chloride (90 ml) was added carbontetrabromide (9.92 g, 29.9 mmol). The mixture was stirred for 1 hour at0° C. and then warmed to ambient temperature over 1 hour. The entiremixture was then loaded onto a flash silica gel column, eluting with 30%ethyl acetate-hexanes to provide 3-nitro-4-(aminophthaloyl)benzylbromide as a yellow-white powder (5.03 g).

Step 6

The conditions for the reduction oftert-butyl-2(R)-[(3-nitro-4-(N-phthalamido)benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino)]-3-[(R)-tert-butyldimethylsilyloxy]-butyrateto providetert-butyl-2(R)-[(3-amino-4-(N-phthalamido)benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino)]-3-[(R)-tert-butyldimethylsilyloxy]-butyrateare the same as those described in Example 10, step 5 above.

Step 7

The conditions for the de-pthaloylation oftert-butyl-2(R)-[(3-amino-4-(N-phthalamido)benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino)]-3-[(R)-tert-butyldimethylsilyloxy]-butyrateto providetert-butyl-2(R)-[3,4-diamino-benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino)]-3-[(R)-tert-butyldimethylsilyloxy]-butyrateare similar to those described in Example 10, step 6 above.

Step 8

The conditions for the clay catalyzed conversion oftert-butyl-2(R)-[3,4-diamino-benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino)]-3-[(R)-tert-butyldimethylsilyloxy]-butyrateto providetert-butyl-2(R)-[benzimidazol-5-yl-methyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino)]-3-[(R)-tert-butyldimethylsilyloxy]-butyrateare similar to those described in Example 10, step 7 above.

Step 9

To a cooled (ice bath) flask containing neattert-butyl-2(R)-[benzimidazol-5-yl-methyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino)]-3-[(R)-tert-butyldimethylsilyloxy]-butyrate(2.53g, 4.0 mmol), under argon was added a 1.0 M solution oftetra-N-butyl-ammonium fluoride (16 ml) via syringe. The mixture wasstirred for 15 minutes at 0° C. and then warmed to ambient temperature.After 30 minutes additional tetra-N-butyl-ammonium fluoride (5 ml) wasadded and stirring continued for 2 hours. To the mixture was added asaturated solution of aqueous ammonium chloride (80 ml) followed byethyl acetate (60 ml). The material was partitioned and the organicphase collected and washed subsequently with three equal volumes ofbrine solution. The aqueous phases were back extracted with ethylacetate (2×80 ml). The organic phases were combined, dried withmagnesium sulfate and condensed. The residue was purified bychromatography (silica gel, ethyl acetate 100% as eluant) providingtert-butyl-2(R)-[benzimidazol-5-yl-methyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino)]-3(R)-hydroxy-butyrateas a viscous clear oil.

Step 10

Tert-butyl-2(R)-[benzimidazol-5-yl-methyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino)]-3(R)-hydroxy-butyratewas converted to2(R)-[benzimidazol-5-yl-methyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino)]-3(R)-hydroxy-butyricacid by following the procedure described in Example 10, step 8 above.

Step 11

2(R)-[benzimidazol-5-yl-methyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino)]-3(R)-hydroxy-butyricacid was then converted toN-hydroxy-2(R)-[benzimidazol-5-yl-methyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino)]-3(R)-hydroxybutyamideby following the procedure as described in Example 3, steps 6 and 7above.

Example 16 Synthesis of Compounds of the following Formula, as shown inScheme E

Step 1

To ArgoGel-OH (formula 1) in a empty solid phase extraction vial, fittedwith a stopcock is added 3 eq. of a compound of formula 2(Fmoc-D-Dpr(BOC)), 3 eq. of diisopropylcarbodiimide (DIC), and 0.05 eq.of a 0.116 M solution of dimethylaminopyridine (DMAP) in THF. SufficientCH₂Cl₂ is added to swell the resin (˜12.5 mL/gr of resin). The reactionis then placed on a spinner and rotated overnight. The reaction is thenfiltered by suction filtration and washed 3 times with CH₂Cl₂, 3 timeswith MeOH, once with 1:1 HOAc/CH₂Cl₂, 3 times with MeOH and then lastly3 times with CH₂Cl₂ and dried to give a resin AG-D-Dpr(BOC)-Fmoc.

The resulting resin (AG-D-Dpr(BOC)-Fmoc) is treated with a solution of20% piperidine in DMF (pip/DMF) for 20 min. The reaction is thenfiltered by suction filtration and washed 3 times with CH₂Cl₂, 3 timeswith MeOH, once with 1:1 HOAc/CH₂Cl₂, 3 times with MeOH and then lastly3 times with CH₂Cl₂. To give a resin of formula 3 (AG-D-Dpr(BOC)-NH₂).

Step 2

To a resin of formula 3 (AG-D-Dpr(BOC)-NH₂) is added sufficient CH₂Cl₂to swell the resin (˜12.5 mL/gr of resin). Then 3 eq. of a sulfonylchloride of formula 4 (Ar²SO₂Cl) and 3 eq. of triethylamine (TEA) areadded. The reaction is then placed on a spinner and rotated overnight.The reaction is then filtered by suction filtration and washed 3 timeswith CH₂Cl₂, 3 times with MeOH, once with 1:1 HOAc/CH₂Cl₂, 3 times withMeOH and then lastly 3 times with CH₂Cl₂ to give a resin of formula 5(AG-D-Dpr(BOC)-NHSO₂Ar²).

Step 3

To the resin of formula 5 (AG-D-Dpr(BOC)-NHSO₂Ar²) is added sufficient1:1 toluene/CH₂Cl₂ to swell the resin (˜12.5 mL/gr of resin). Then 10eq. of 1,1′-(azodicarbonyl)dipiperidine (ADDP), 10 eq. of Bu₃P, followedby 10 eq. of piperonyl alcohol (ROH) are added. The reaction is thenplaced on a spinner and rotated overnight. The reaction is then filteredby suction filtration and washed 3 times with CH₂Cl₂, 3 times with MeOH,once with 1:1 HOAc/CH₂Cl₂, 3 times with MeOH and then lastly 3 timeswith CH₂Cl₂ to give a resin of formula 6 (AG-D-Dpr(BOC)-NRSO₂Ar²).

Step 4

The resin of formula 6 (AG-D-Dpr(BOC)-NRSO₂Ar²) is treated with asolution of 1M chlorotrimethylsilane in 3M phenol/CH₂Cl₂ for 30 minutes.The reaction is then filtered by suction filtration and washed 3 timeswith CH₂Cl₂, 3 times with MeOH, once with 1:1 HOAc/CH₂Cl₂, 3 times withMeOH and then lastly 3 times with CH₂Cl₂ to give a resin of formula 7(AG-D-Dpr-NRSO₂Ar²).

Step 5

To a resin of formula 7 (AG-D-Dpr-NRSO₂Ar²) is added 3 eq. of asuccinimidylcarbonate of formula 8 (R″OCO₂Su), 3 eq. Et₃N (TEA) and 0.05eq. of a 0.116 M solution of 4-dimethylaminopyridine (DMAP) in THF.Sufficient CH₂Cl₂ is added to swell the resin (˜12.5 mL/gr of resin).The reaction is then placed on a spinner and rotated overnight. Thereaction is then filtered by suction filtration and washed 3 times withCH₂Cl₂, 3 times with MeOH, once with 1:1 HOAc/CH₂Cl₂, 3 times with MeOHand then lastly 3 times with CH₂Cl₂ to give a resin of formula 9(AG-D-Dpr(COOR″)-NRSO₂Ar²).

Step 6

A resin of formula 9 (AG-D-Dpr(COOR″)-NRSO₂Ar²) is first washed withTHF. Sufficient THF is added to swell the resin (˜12.5 mL/gr of resin).Then 25 eq. of 50% aq. NH₂OH is added and the reaction is rotated fortwo days. The reaction is then filtered by suction filtration and washedwith CH₂Cl₂, MeOH, and then CH₂Cl₂. The filtrate is concentrated on aSpeed Vac to obtain a compound of formula 10 (HONH-Dpr(COOR″)NRSO₂Ar²),which is purified by RP-HPLC.

Using the appropriate sulfonyl chloride of formula 4 and the appropriatesuccinimidylcarbonate of formula 8, the following compounds of Table Iwere made:

Compound 139, Compound 140, Compound 141, Compound 146, Compound 148,and Compound 149.

Example 17 Synthesis of Compounds of the following Formula, as shown inScheme F

Step 1

A resin of formula 7 (AG-D-Dpr-NRSO₂Ar²) is first washed with THF, then15 eq. of the isocyanate of formula 8 (ArNCO) is added. Sufficient THFis added to swell the resin (˜12.5 mL/gr of resin). The reaction is thenplaced on a spinner and rotated overnight. The reaction is then filteredby suction filtration and washed 3 times with CH₂Cl₂, 3 times with MeOH,once with 1:1 HOAc/CH₂Cl₂, 3 times with MeOH and then lastly 3 timeswith CH₂Cl₂ to give a resin of formula 9 (AG-D-Dpr(CONHAr)-NRSO₂Ar²).

Step 2

A resin of formula 9 (AG-D-Dpr(CONHAr)-NRSO₂Ar²) is first washed withTHF. Sufficient THF is added to swell the resin (˜12.5 mL/gr of resin)then 25 eq. of 50% aq. NH₂OH is added and the reaction is rotated fortwo days. The reaction is then filtered by suction filtration and washedwith CH₂Cl₂, MeOH, and then CH₂Cl₂. The filtrate is concentrated on aSpeed Vac to obtain a compound of formula 10 (HONH-Dpr(CONHAr)NRSO₂Ar²),which is purified by RP-HPLC.

Using the appropriate isocyanate of formula 8 the following compound ofTable I was made:

Compound 147.

Example 18 Formulation Examples

The following are representative pharmaceutical formulations containinga compound of Formula (I).

Tablet Formulation

The following ingredients are mixed intimately and pressed into singlescored tablets.

Quantity per Ingredient tablet, mg compound of this invention 400cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5

Capsule Formulation

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule.

Quantity per Ingredient capsule, mg compound of this invention 200lactose, spray-dried 148 magnesium stearate 2

Suspension Formulation

The following ingredients are mixed to form a suspension for oraladministration.

Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 gsodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 ggranulated sugar 25.5 g sorbitol (70% solution) 12.85 g Veegum K(Vanderbilt Co.) 1.0 g flavoring 0.035 ml colorings 0.5 mg distilledwater q.s. to 100 ml

Injectable Formulation

The following ingredients are mixed to form an injectable formulation.

Ingredient Amount compound of this invention 0.2 g sodium acetate buffersolution, 0.4M 2.0 ml HCl (1N) or NaOH (1N) q.s. to suitable pH water(distilled, sterile) q.s. to 20 ml

Liposomal Formulation

The following ingredients are mixed to form a liposomal formulation.

Ingredient Amount compound of this invention  10 mgL-α-phosphatidylcholine 150 mg tert-butanol  4 ml

Freeze dry the sample and lyopholize overnight. Reconstitute the samplewith 1 ml 0.9% saline solution. Liposome size can be reduced bysonication

Example 19 Isolation and Preparation of Procollagen C-Proteinase

Cloning of Human PCP and Construction of the HT-1080 Vector

Human Procollagen C-Proteinase (PCP, also known as Bone MorphogeneticProtein-1 or BMP-1) was cloned from a human fibroblast cDNA library(Stratagene, San Diego, Calif.). Cloning was performed by PCR based onthe reported nucleotide sequence (Wozney, J. M., Rosen,V., Celeste, A.J., Mitsock, L. M., Whitters, M. J., Kriz, R. W., Hewick, R. M., andWang, E. A. (1989) direct GenBank submission accession M22488, locusHUMBMP1) using Taq polymerase, the 5′ primerGCGCGCGGTACCCGCCCCGCCAGCATGCCCGGCGTGGCCCGCCTGCCGCTGCTGCTCGGGCTGCTGCTGCTCCCGCGTCCCGGCCGGCCGCTGGACTTGGCCGACTACACCTATGACCTGGC(SEQ ID NO:1) (Oligo Therapeutics, Inc., Wilsonville, Oreg.), and the 3′reverse strand primerCCGCTCGAGCCTCACTGGGGGGTCCGGTTTCTTTTCTGCACTCGGAATTTGAGCTGGTG (SEQ IDNO:2) (Gibco) to yield the entire full-length nucleotide encoding thesignal sequence, propeptide, catalytic domain, and all C-terminaldomains to the natural translation termination site. The PCR product waspurified by gel electrophoresis using the Wizard DNA Purification Kit(Promega, Madison, Wis.) and ligated directly into the mammalianexpression vector pCR3.1 (Invitrogen, Carlsbad, Calif.) by the TAcloning method. Ligated product was used to transform E coli strainTOP10F′ (Invitrogen, Carlsbad, Calif.) by a standard heat-shock method,and transformants were selected by restriction analysis of purifiedplasmid using the enzymes HindIII and BamHI. Transformants testingpositive for the PCP insert were submitted for sequencing using thePerkin-Elmer/ABI system. Two clones were selected that, when combined,encoded the entire amino acid sequence identical to the one predicted byWozney et al. The two clones were recombined by restriction using theenzymes BbrI, which cleaved at a naturally occurring internal site, andEcoRV, which cleaved at the junction of the insert and vector. Theexcised fragments were religated into EcoRV-treated pCR3.1. Theresulting construct contained the entire coding sequence identical tothat reported by Wozney et al. with the exception of two silentmutations in the signal sequence, G→A at both positions 39 and 45counting from the translation initiation site (ATG). The completedplasmid construct was amplified in E. coli DH5a and purified using anionexchange chromatography (MaxiPrep columns from Qiagen (Valencia, Calif.)catalog #12162).

Transfection of HT-1080 and Selection of the PCP-expressing Clone

The human fibrosarcoma line HT-1080 (ATCC) was grown in high glucoseDEEM (DMEM-HG) supplemented with 10% heat-inactivated fetal bovine serum(HI-FBS) in 100 mm culture dishes (Falcon, Becton Dickenson, Franklin,N.J.) and transfected with 2 μg of purified plasmid using the standardmethod for Lipofectamine (Gibco, Bethesda, Md.) in serum free medium.Stable transfectants were selected by treating the plated culture with400 μg/ml G418 (Gibco). After selection for 10 days, the adherent singlecolonies were picked from the plate, replated in 12-well plates andgrown until confluent. Individual stable colonies were screened for PCPexpression by TaqMan (Perkin-Elmer, Foster City, Calif.) analysis usingequivalent amounts of total RNA, the 5′ primer GACGAAGAGGACCTGAGGGCCTT(SEQ ID NO:3) (Perkin-Elmer, Foster City, Calif.), the 3′ reverse strandprimer TTCCTGGAACTGCAGCTTTGA (SEQ ID NO:4) (Perkin-Elmer, Foster City,Calif.), and the reverse strand probe TGCCGTCTGAGATCCACAGCCTGCT (SEQ IDNO:5) (Perkin-Elmer). A stable line, HT-1080/hPCP-23, was chosen basedon the highest PCP mRNA expression level in the TaqMan screen. Stocks ofthe HT-1080/hPCP-23 stable line were transferred to DMEM-HG supplementedwith 5% HI-FBS and 10% DMSO (no G 418 added) and were slowly frozen at−70° C. overnight, then transferred to a liquid nitrogen bath forlong-term storage. Revitalized HT-1080/hPCP-23 were maintained inDMEM-HG supplemented with 10% HI-FBS and 250 μg/ml G418 for no more than7 passages. Expression of PCP for harvest was carried out by replatingand growing HT-1080/hPCP-23 on rat tail type I collagen-coated plates(Falcon) in OptiMEM (Gibco) serum free medium without G418 for 24 hr.

Production of PCP in HT1080 Cells

The HT1080 cells that were transformed to produce PCP were adapted togrow in suspension in optiMEM medium (GIBCO) supplemented with 5% fetalbovine serum and 4 ml/L G418 (GIBCO). The culture was maintained at 37C. and the dissolved oxygen at 30%. Typically batch sizes of 10 literswere produced. When the cell density reached 4-6×10⁵ cells/ml, theculture fluid was collected and filtered through 0.2 μm membranes.Alternatively, the cell culture was perfused with fresh media at therate of 0.8 to 1.0 culture volume/day. The density of the perfusedcultures reached 1-2.5×10⁶ cells/ml and were maintained up to two weekswith continuous harvests.

Purification of PCP from HT1080 Cells

A column packed with Dyematrex Gel Green A (Millipore, Bedford, Mass.)was equilibrated against 50 mM HEPES, pH7.2, containing 6 mM CaCl₂ and0.3M NaCl. After the HT1080 cell culture fluid was loaded, the columnwas washed with 10 column volumes of the equilibration buffer containing1.0 M NaCl. PCP was eluted with 50 mM HEPES pH 7.2 containing 3 M NaCl,2 M urea and 6 mM CaCl₂. Eluate fractions were pooled and concentratedto 150-200 ml and dialyzed against 4.0 liters of 50 mM HEPES, 6 mMCaCl₂, pH 7.2 overnight. The material was then centrifuged at 5,000 gfor 15 minutes to remove precipitates. The PCP containing sample werestored at −20° C. until ready for further processing.

The PCP containing sample was thawed and diluted with 50 mM HEPES pH 7.2containing 6 mM CaCl₂, if necessary to bring the NaCl concentration to0.1-0.15 M. The pH was adjusted to 6.7 with 2 N HCl. The proteinsolution was filtered through a 0.45 μm filter to remove anyprecipitate. This preparation was then loaded onto a column packed withQ-Sepharose High Performance (Pharmacia, Piscataway, N.J.) which hadbeen equilibrated with 50 mM HEPES pH 6.7 containing 6 mM CaCl₂ and 0.15M NaCl. The PCP was not retained in the column and was therefore in theflow through fractions. The PCP was concentrated to 1 mg/ml and used forscreening.

Production of PCP in Drosophila Cells

Drosophila cells which had been transformed to produce PCP were grown inbioreactors at a typical batch volume of 10 liters in SF900 II SF medium(GIBCO). The temperature was maintained at 30° C. and the dissolvedoxygen at 30%. Periodically the cells were fed a cocktail consisting ofglutamine, lipids and yeastolate. When cell densities reached 30-50×10⁶cells/ml, supernatants were harvested by centrifugation and concentratedby ultrafiltration using a 30 Kd membrane.

Purification of PCP from Culture Fluid from Drosophila Cells

Culture fluid from the drosophila cells was concentrated 8 fold and thepH adjusted to 7.1-7.2 if necessary. The culture fluid was centrifugedat 3000 g for 10 minutes and filtered through 0.45 μm filters. Theculture fluid was then loaded onto columns packed with carboxy-sulfonepacking material (J. T. Baker/Mallinckrodt, Phillipsburg, N.J.) whichhad been equilibrated with 0.1 M NaCl, 50 mM HEPES, 6 mM CaCl₂, pH 7.2.After being loaded, the column was washed with 10 column volumes of theequilibration buffer. Retained proteins were eluted with a gradient of0.1 to 1.0 M NaCl in 9 column volumes. Fractions that had PCP activitywere pooled for further purification.

The PCP eluted off the carboxy-sulfone column was loaded onto aDyematrex Gel Green A (Millipore, Bedford, Mass.) column that had beenequilibrated with 50 mM HEPES, pH 7.4 containing 0.3 M NaCl and 6 mMCaCl₂. The column was then washed with the equilibration buffercontaining 1 M NaCl. Retained proteins were eluted with 50 mM HEPES, pH7.4, 3 M NaCl, 2 M urea, 6 mM CaCl₂. The elution peak was concentratedand dialyzed against 50 mM HEPES, pH 7.4 containing 0.3 M NaCl, 6 mMCaCl₂. The preparation was centrifuged at 3000 g for 10 minutes. Brij 35(Sigma, Madison, Wis.) was added to the supernatant to a finalconcentration of 0.02%. This preparation was used for screening.

Example 20 Isolation of Collagenase Enzymes

The catalytic domain of human collagenase-1 was expressed as a fusionprotein with ubiquitin in E. coli as described in Gehring, E. R. et al.,J. Biol. Chem., 270, 22507, (1995). After purification of the fusionprotein, the collagenase-1 catalytic domain was released by treatmentwith 1 mM of aminophenylmercuric acetate (APMA) for 1 hour at 37° C. andthen purified by zinc chelate chromatography.

Human collagenase-2 and gelatinase B were isolated in active form frombuffy coats as described in Mookhtiar, K. A. et al., Biochemistry, 29,10620, (1990).

The propeptide and catalytic domain portion of human collagenase-3 wasexpressed in E. coli as an N-terminal fusion protein with ubiquitin.After purification, the catalytic domain was released by treatment with1 mM APMA for 1 hour at 37° C., and then purified by zinc chelatechromatography.

Rat collagenase-3 was purified in active form from the culture media ofuterine smooth muscle cells as described in Roswit, W. T. et al., Arch.Biochem. Biophys., 225, 285-295 (1983).

Example 21 Inhibition of Procollagen C-Proteinase Activity

The ability of the compounds to inhibit PCP has been demonstrated in thefollowing in vitro assays utilizing a synthetic peptide as thesubstrate.

Assay A

A continuous assay was performed using 20 μM substrate(Dabcyl-Pro-Tyr-Tyr-Gly-Asp-Glu-Pro-n-Leu-Edans) (SEQ ID NO:6). Thefinal assay conditions were 20 μM substrate, 50 mM HEPES pH 7.5, 50 mMNaCl, 3% DMSO, 30° C. and PCP enzyme. Product formation was monitored byfluorescence spectroscopy, Ex.=335 nm, Em.=490 nm. The IC₅₀ wascalculated from the dose response of the compounds.

Assay B

Eighty μL of buffer A (20 mM HEPES) containing the desiredconcentrations of the test compound in DMSO or carrier vehicle was mixedwith 10 μL of approx. 1 mg/mL PCP enzyme and 10 μL of 0.1 mM substrateboth in 20 mM HEPES. The contents are mixed, incubated at roomtemperature for 1-2 hours and fluorescent readings taken with a Victorplate reader (Ex. 405 nm, Em. 460 nM at 2000-40,000 lamp energy, 0.1-1sec/well). The substrate wasDACM-Cys-Pro-Tyr-Gly-Asp-Glu-Pro-nLeu-Lys-FITC-OH. (SEQ ID NO:7)(DACM=dimethylaminocoumarylmaleimide, FITC=fluorescein isothiocyanate).The IC₅₀ was calculated from plots of the initial velocity vs. compoundconcentration.

Additional in vitro assays using native procollagen as the substrate mayalso be used and these assays are described in more detail in WO97/05865 (“C-Proteinase Inhibitors for the Treatment of DisordersRelating to the Overproduction of Collagen”), published 20 Feb. 1997.

The compounds in Table I had IC₅₀'s in the range of 0.01 to 2 μM.

Example 22 Measurement of Collagenase Activity

The collagenase-1, collagenase-2 and collagenase-3 inhibitory activityof compounds of this invention in vitro was determined based on thehydrolysis of MCA-Pro-Leu-Gly-Leu-DPA-Ala-Arg-NH₂ (SEQ ID NO:8) (Bachem,Inc.) at 37° C. as described in Knight, C. G., et al., FEBS Lett.,296(3): 263-266 (1992).

The collagenase enzyme was diluted with assay buffer (50 mM Tricine pH7.5, 200 mM NaCl, 10 mM CaCl₂, and 0.005% Brij-35) containing 10 μmoleof above substrate dissolved in DMSO. Compounds of the inventiondissolved in DMSO or only DMSO (control samples) were added such thatthe final DMSO concentration in all assays was 2.5%. The fluorescencechanges were monitored with a Perkin-Elmer LS-50B flourimeter using anexcitation wavelength of 328 nm and an emission wavelength of 393 nm.

Selected compounds from Tables I were 100-1000 more selective for PCPinhibition than for the collagenase-1 and collagenase-3 enzymes and50-500 more selective for PCP inhibition than for the collagenase-1 andcollagenase-2 enzymes.

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

8 1 122 DNA Artificial Sequence pcr primer 1 gcgcgcggta cccgccccgccagcatgccc ggcgtggccc gcctgccgct gctgctcggg 60 ctgctgctgc tcccgcgtcccggccggccg ctggacttgg ccgactacac ctatgacctg 120 gc 122 2 59 DNAArtificial Sequence pcr primer 2 ccgctcgagc ctcactgggg ggtccggtttcttttctgca ctcggaattt gagctggtg 59 3 23 DNA Artificial Sequence pcrprimer 3 gacgaagagg acctgagggc ctt 23 4 21 DNA Artificial Sequence pcrprimer 4 ttcctggaac tgcagctttg a 21 5 25 DNA Artificial Sequence pcrprimer 5 tgccgtctga gatccacagc ctgct 25 6 8 PRT Artificial Sequencesynthetic peptide 6 Pro Tyr Tyr Gly Asp Glu Pro Leu 1 5 7 9 PRTArtificial Sequence synthetic peptide 7 Cys Pro Tyr Gly Asp Glu Pro LeuLys 1 5 8 7 PRT Artificial Sequence synthetic peptide 8 Arg Ala Xaa LeuGly Leu Pro 1 5

What is claimed:
 1. A compound selected from the compounds of Formula(I):

wherein: Z is —OH or OR¹² wherein R¹² is alkyl; R¹ is alkyl, haloalkyl,cycloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl,heteroaralkenyl, heterocyclylalkyl, cycloalkylalkyl, -(alkylene)-C(O)—Xwhere X is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, amino,monosubstituted amino, disubstituted amino, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy,cycloalkoxy, cycloalkylalkoxy, heteroalkyloxy, aralkyloxy, orheteroaralkyloxy), —C(═NR′)NHSO₂R″ (where R′ is hydrogen or alkyl, andR″ is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, or heterocyclylalkyl), or heteroalkyl,wherein said heteroalkyl is an alkyl, cycloalkyl, or cycloalkylalkylcarrying a substituent selected from —NR^(a)R^(b), —OR^(c), or—S(O)_(n)R^(d) wherein n is an integer from 0 to 2; R^(a) is hydrogen,alkyl, or —COR (where R is hydrogen, alkyl, or haloalkyl); R^(b) ishydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,heterocyclyhydroxyalkyl, —COR (where R is hydrogen, alkyl, haloalkyl,monosubstituted aminoalkyl, aryloxyalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylalkyl), or-(alkylene)-C(O)—X (where X is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino,aryl), aralkyl, heteroaryl, heteroalkyl, heterocyclyl, orheterocyclyalkyl), —SO₂R (where R is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,heterocyclylalkyl, amino, monosubstituted amino or disubstituted amino),—COOR (where R is hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, orheterocyclylalkyl), —CONR′R″, or -(alkylene)-CONR′R″ [where R′ and R″are independently selected from hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl,or SO₂R (where R is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,amino, monosubstituted amino or disubstituted amino), or R′ and R″together with the nitrogen atom to which they are attached form aheterocyclyl ring]; R^(c) hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroalkyl,heterocyclylalkyl, —COR (where R is alkyl, haloalkyl, or heteroalkyl),or —CONR′R″ (where R′ and R″ are independently selected from hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl); and R^(d) is hydrogen (provided that n is 0), alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, amino, monosubstituted amino, ordisubstituted amino; and R^(d) is hydrogen (provided that n is 0),alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, amino, monosubstitutedamino, or disubstituted amino; R is —CH(R²)Ar¹ or —CH(R²)CH═CHAr¹ whereR² is hydrogen or alkyl; and Ar¹ is heteroaryl selected from indol-5-yl,1-methylindol-5-yl, 3acetylindol-5-yl, 3-propionylindol-5-yl,3-(2-methylpropionyl)indol-5-yl, imidazol-5-yl,2-methylbenzimidazol-5-yl, benzimidazol-5-yl, benzoxazol-5-yl,3-[1-(hydroxymino)propyl]indol-5-yl, and3-[(N-benzyloxy)methylimidoyl]indol-5-yl; Ar² is either; (i) a phenylring of formula (a):

wherein: R³ and R⁷ are, independently of each other, hydrogen, alkyl,alkylthio, or halo; R⁴ and R⁶ are, independently of each other,hydrogen, alkyl, or halo; R⁵ is alkyl, haloalkyl, heterocyclyl,alkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio,cycloalkylthio, cycloalkylalkylthio, alkoxy, aryloxy, aralkoxy,heteroaryloxy, heteroaralkyloxy, cycloalkoxy, cycloalkylalkoxy,alkyloxycarbonyl, hydroxy, halo, cyano, carboxy, nitro, amino,monoalkylamino, dialkylamino, alkylsulfonyl, arylsulfonyl,aralkylsulfonyl, heteroarylsulfonyl, heteroaralkylsulfonyl,cycloalkylsulfonyl, cycloalkylalkylsulfonyl, or —Y-(alkylene)-C(O)—Z[where Y is a bond, —NR^(a)—, —O—, or —S(O)_(n)— (where n is 0 to 2), R⁸is hydrogen or alkyl, and Z is alkoxy, hydroxy, amino, monosubstitutedamino, or disubstituted amino]; or R³ together with R⁴ forms—O—(CR⁸R⁹)_(n)— where n is 2 or 3 and each R⁸ and R⁹ are, independentlyof each other, hydrogen or alkyl; or the carbon atoms to which R⁵ and R⁴are attached are fused to the C2-C3 carbons of a benzofuran ring;provided that at least two of R³, R⁴, R⁶, and R⁷ are not hydrogen at thesame time; or (ii) a naphthyl ring of formula (b):

wherein: R¹⁰ is hydrogen, alkyl, alkoxy, or halo; and R¹¹ is hydrogen,alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy, hydroxy,halo, cyano, carboxy, nitro, amino, monoalkylamino, dialkylamino oralkylsulfonyl provided that both R¹⁰ and R¹¹ are not hydrogen at thesame time; and their pharmaceutically acceptable salts, prodrugs,individual isomers, and mixtures of isomers.
 2. The compound of claim 1wherein R is —CH(R²)Ar¹ wherein R² is hydrogen.
 3. The compound of claim2 wherein: R³ and R⁷ are, independently of each other, alkyl, alkylthio,or halo; R⁴ is hydrogen, alkyl, or halo; R⁵ is alkyl, haloalkyl,alkylthio, alkoxy, alkyloxycarbonyl, aryloxy, hydroxy, halo, cyano,carboxy, nitro, amino, monoalkylamino, dialkylamino, or alkylsulfonyl;and R⁶ is hydrogen.
 4. The compound of claim 3 wherein: R³ and R⁷ are,independently of each other, alkyl or halo; R⁴ is alkyl; and R⁵ isalkyl, alkoxy, or halo.
 5. The compound of claim 4 wherein: R³, R⁴, andR⁷ are methyl; and R⁵ is methoxy, chloro, or bromo.
 6. The compound ofclaim 5 wherein R¹ is alkyl, aralkyl, or -(alkylene)-C(O)—X where X isalkyl, amino, monosubstituted amino, disubstituted amino, orheterocyclyl, or heteroalkyl wherein said heteroalkyl is an alkyl,cycloalkyl, or cycloalkylalkyl carrying a substituted selected from—NR^(a)R^(b), —OR^(c), or —S(O)_(n)R^(d) wherein n is an integer from 0to 2; R^(a) is hydrogen, alkyl, or —COR (where R is hydrogen, alkyl, orhaloalkyl); R^(b) is hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,heterocyclylalkyl, heterocyclyhydroxyalkyl, —COR (where R is hydrogen,alkyl, haloalkyl, monosubstituted aminoalkyl, aryloxyalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclylalkyl, or -(alkylene)-C(O)—X (where X is alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstitutedamino, aryl, aralkyl, heteroaryl, heteroalkyl, heterocyclyl, orheterocyclyalkyl), —SO₂R (where R is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,heterocyclylalkyl, amino, monosubstituted amino or disubstituted amino),—COOR (where R is hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, orheterocyclylalkyl), —CONR′R″, or -(alkylene)-CONR′R″ [where R′ and R″are independently selected from hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl,or SO₂R (where R is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,amino, monosubstituted amino or disubstituted amino), or R′ and R″together with the nitrogen atom to which they are attached form aheterocyclyl ring]; R^(c) hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroalkyl, heteroaralkyl,heterocyclylalkyl, —COR (where R is alkyl, haloalkyl, or heteroalkyl),or —CONR′R″ (where R′ and R″ are independently selected from hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl); and R^(d) is hydrogen (provided that n is 0), alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, amino, monosubstituted amino, ordisubstituted amino; and R^(d) is hydrogen (provided that n is 0),alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, amino, monosubstitutedamino or disubstituted amino.
 7. The compound of claim 6 wherein R¹ is2-propyl, hydroxymethyl, tert-butoxymethyl, 2-hydroxyethyl,2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl, methoxymethyl,or -(alkylene)-C(O)—X where X is 2- or 4-pyridylmethylamino,1-alkoxycarbonylpyridin-4-ylamino, optionally substituted benzylamino,4-optionally substituted benzyloxycarbonylpiperazin-1-yl, 4-optionallysubstituted phenylpiperazin-1-yl, 4-alkoxycarbonylpiperazin-1-yl, or4-optionally substituted heteroarylpiperazin-1-yl.
 8. The compound ofclaim 4 wherein R¹ is -(alkylene)-C(O)—X where X is alkyl, amino,monosubstituted amino, disubstituted amino, or heterocyclyl, orheteroalkyl, wherein said heteroalkyl is an alkyl, cycloalkyl, orcycloalkylalkyl carrying a substituted selected from —NR^(a)R^(b),—OR^(c), or —S(O)_(n)R^(d) wherein n is an integer from 0 to 2; R^(a) ishydrogen, alkyl, or —COR (where R is hydrogen, alkyl, or haloalkyl);R^(b) is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,heterocyclyhydroxyalkyl, —COR (where R is hydrogen, alkyl, haloalkyl,monosubstituted aminoalkyl, aryloxyalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylalkyl), or-(alkylene)-C(O)—X (where X is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino,aryl, aralkyl, heteroaryl, heteroalkyl, heterocyclyl, orheterocyclyalkyl), —SO₂R (where R is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,heterocyclylalkyl, amino, monosubstituted amino or disubstituted amino),—COOR (where R is hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, orheterocyclylalkyl), —CONR′R″, or -(alkylene)-CONR′R″ [where R′ and R″are independently selected from hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl,or SO₂R (where R is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,amino, monosubstituted amino or disubstituted amino), or R′ and R″together with the nitrogen atom to which they are attached form aheterocyclyl ring]; R^(c) hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclylalkyl, —COR (where R is alkyl, haloalkyl, or heterocyclyl),or —CONR′R″ (where R′ and R″ are independently selected from hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl); and R^(d) is hydrogen (provided that n is 0), alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, amino, monosubstituted amino, ordisubstituted amino; and R^(d) is hydrogen (provided that n is 0),alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroararyl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, amino, monosubstitutedamino, or disubstituted amino.
 9. The compound of claim 8 wherein R¹ ismethylsulfonylaminomethyl, phenylsulfonylaminomethyl,(3-nitrophenyl)CH₂SO₂NHCH₂—, methylcarbonylaminomethyl,4-(methoxycarbonyl)phenylcarbonylaminomethyl,2-(pyrrol-1-yl)phenylcarbonylaminomethyl,3-cyanophenylaminocarbonylaminomethyl, thien-2-ylcarbonylaminomethyl,phenylcarbonylaminomethyl, (C₆H₅)CHCH₃NHCO(C₂H₄)CONHCH₂—,(4-methoxyphenyl)COC₂H₄CONHCH₂—,4-chlorophenylsulfonylaminocarbonylaminomethyl,5-(acetyl)thien-2-ylcarbonylaminomethyl,pyridin-3-ylcarbonylaminomethyl, (3,4,5-trimethoxyphenyl)C₂H₄CONHCH₂—,3-methoxyphenylaminocarbonylaminomethyl, (phenoxy)CH(CH₂CH₃)CONHCH₂—,1-(ethoxycarbonyl)piperidin-4-yl-aminomethylcarbonylaminomethyl,3-(benzyloxycarbonylamino)propyl,2-[(diphenyl)methylaminocarbonyl]ethyl,2-[2-(methyl)butylaminocarbonyl]ethyl, or 2-[(C₆H₅)CHCH₃NHCO]ethyl. 10.The compound of claim 1 wherein: R⁴ and R⁶ are hydrogen; R³ and R⁷ are,independently of each other, alkyl, or halo; and R⁵ is alkyl, haloalkyl,alkylthio, alkoxy, alkyloxycarbonyl, aryloxy, hydroxy, halo, cyano,carboxy, nitro, amino, monoalkylamino, dialkylamino, or alkylsulfonyl.11. The compound of claim 5 wherein; R³ is alkyl; R⁵ is alkyl, alkoxy,or halo; and R⁷ is alkyl or halo.
 12. The compound of claim 11 wherein:R³ and R⁷ are methyl; and R⁵ is methoxy, chloro, or bromo.
 13. Thecompound of claim 12 wherein R¹ is alkyl, aralkyl, -(alkylene)-C(O)—Xwhere X is alkyl, amino, monosubstituted amino, disubstituted amino,heterocyclyl, or heteroalkyl wherein said heteroalkyl is an alkyl,cycloalkyl, or cycloalkylalkyl carrying a substituted selected from—NR^(a)R^(b), —OR^(c), or —S(O)_(n)R^(d) wherein n is an integer from 0to 2; R^(a) is hydrogen, alkyl, or —COR (where R is hydrogen, alkyl, orhaloalkyl); R^(b) is hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,heterocyclylalkyl, heterocyclyhydroxyalkyl, —COR (where R is hydrogen,alkyl, haloalkyl, monosubstituted aminoalkyl, aryloxyalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclylalkyl, or -(alkylene)-C(O)—X (where X is alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstitutedamino, aryl, aralkyl, heteroaryl, heteroalkyl, heterocyclyl, orheterocyclyalkyl), —SO₂R (where R is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaryl, heterocyclyl,heterocyclylalkyl, amino, monosubstituted amino or disubstituted amino),—COOR (where R is hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, orheterocyclylalkyl), —CONR′R″, or -(alkylene)-CONR′R″ [where R′ and R″are independently selected from hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl,or SO₂R (where R is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,amino, monosubstituted amino or disubstituted amino), or R′ and R″together with the nitrogen atom to which they are attached form aheterocyclyl ring]; R^(c) hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclylalkyl, —COR (where R is alkyl, haloalkyl, or heterocyclyl),or —CONR′R″ (where R′ and R″ are independently selected from hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl); and R^(d) is hydrogen (provided that n is 0), alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, amino, monosubstituted amino, ordisubstituted amino; and R^(d) is hydrogen (provided that n is 0),alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, amino, monosubstitutedamino, or disubstituted amino.
 14. The compound of claim 13 wherein R¹is 2-propyl, hydroxymethyl, tert-butoxymethyl, 2-hydroxyethyl,2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl, methoxymethyl,or -(alkylene)-C(O)—X where X is 2- or 4-pyridylmethylamino,1-alkoxycarbonylpyridin-4-ylamino, optionally substituted benzylamino,4-optionally substituted benzyloxycarbonylpiperazin-1-yl, 4-optionallysubstituted phenylpiperazin-1-yl, 4-alkoxycarbonylpiperazin-1-yl, or4-optionally substituted heteroarylpiperazin-1-yl.
 15. The compound ofclaim 12 wherein R¹ is -(alkylene)-C(O)—X where X is alkyl, amino,monosubstituted amino, disubstituted amino, or heterocyclyl, orheteroalkyl wherein said heteroalkyl is an alkyl, cycloalkyl, orcycloalkylalkyl carrying a substituted selected from —NR^(a)R^(b),—OR^(c), or —S(O)_(n)R^(d) wherein n is an integer from 0 to 2; R^(a) ishydrogen, alkyl, or —COR (where R is hydrogen, alkyl, or haloalkyl);R^(b) is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,heterocyclyhydroxyalkyl, —COR (where R is hydrogen, alkyl, haloalkyl,monosubstituted aminoalkyl, aryloxyalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylalkyl, or-(alkylene)-C(O)—X (where X is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino,aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, orheterocyclyalkyl), —SO₂R (where R is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,heterocyclylalkyl, amino, monosubstituted amino or disubstituted amino),—COOR (where R is hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, orheterocyclylalkyl), —CONR′R″, or -(alkylene)-CONR′R″ [where R′ and R″are independently selected from hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl,or SO₂R (where R is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,amino, monosubstituted amino or disubstituted amino), or R′ and R″together with the nitrogen atom to which they are attached form aheterocyclyl ring]; R^(c) hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclylalkyl, —COR (where R is alkyl, haloalkyl, or heterocyclyl),or —CONR′R″ (where R′ and R″ are independently selected from hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl); and R^(d) is hydrogen (provided that n is 0), alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, amino, monosubstituted amino, ordisubstituted amino; and R^(d) is hydrogen (provided that n is 0),alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, amino, monosubstitutedamino, or disubstituted amino.
 16. The compound of claim 15 wherein R¹is methylsulfonylaminomethyl, phenylsulfonylaminomethyl,(3-nitrophenyl)CH₂SO₂NHCH₂, methylcarbonylaminomethyl,4-(methoxycarbonyl)phenylcarbonylaminomethyl,2-(pyrrol-1-yl)phenylcarbonylaminomethyl,3-cyanophenylaminocarbonylaminomethyl, thien-2-ylcarbonylaminomethyl,phenylcarbonylaminomethyl, (C₆H₅)CHCH₃NHCO(C₂H₄)CONHCH₂—,(4-methoxyphenyl)COC₂H₄CONHCH₂,4-chlorophenylsulfonylaminocarbonylaminomethyl,5-(acetyl)thien-2-ylcarbonylaminomethyl,pyridin-3-ylcarbonylaminomethyl, (3,4,5-trimethoxyphenyl)C₂H₄CONHCH₂—,3-methoxyphenylaminocarbonylaminomethyl, (phenoxy)CH(CH₂CH₃)CONHCH₂—,1-(ethoxycarbonyl)piperidin-4-yl-aminomethylcarbonylaminomethyl,3-(benzyloxycarbonylamino)propyl,2-[(diphenyl)methylaminocarbonyl]ethyl,2-[2-(methyl)butylaminocarbonyl]ethyl, or 2-[(C₆H₅)CHCH₃NHCO]ethyl. 17.The compound of claim 1 wherein Ar² is a naphthyl ring of formula (b).18. The compound of claim 1 wherein R is —CH(R²)CH═CHAr¹ wherein R² ishydrogen.
 19. The compound of claim 18 wherein Ar² is a phenyl ring offormula (a).
 20. The compound of claim 18 wherein Ar² is a naphthyl ringof formula (b).